Lecture 24 Flashcards
(23 cards)
Where does the production of testosterone occur (in what cells?) and what hormone stimulates the synthesis? Testosterone can get converted into what other two molecules after it is synthesized?
Synthesis of testosterone occurs in the leydig cells, stimulated by luteinizing hormone (LH.) Testosterone is able to be converted into 5alpha-dihydrotestosterone (through 5alpha-reductase) or estradiol/estrogen (through aromatase) depending on the tissue and what is needed.
1) What other organ/gland produced testosterone other than the testis in men?
2) Most of the testosterone produced will target what specific receptors, and where?
3) What happens to testosterone that is converted into 5alpha-dihydrotestosterone? Where does it go?
- what about testosterone that is converted into estrogen?
1) Adrenal cortex in the zona reticularis
2) Most of the testosterone produced by the testis (90-95% goes into circulation) will target androgen receptors in the muscles and allow for the nuclear receptor to bind to DNA and changes in gene expression.
3) 5alpha-dihydrotestosterone will target dihydrotestosterone/androgen receptors which are present the most in the skin and prostate. This can’t be aromatized to estradiol. This is usually what is dysregulated in prostate cancer and male pattern baldness.
- when testosterone is aromatized into estrogen, the estrogen will target estradiol/estrogen receptors which are present the most in the bone and in the brain. (Estradiol is the active form of estrogen.)
What hormone stimulates the production/secretion of testosterone and/or estradiol from the adrenal cortex? What part of the adrenal cortex does this process occur? Explain the synthesis pathway for these hormones.
In the zona reticularis, adrenocorticotropic hormone (ACTH) is going to stimulate the production secretion of testosterone and estradiol.
ACTH binds to a GPCR on the cells of the zona reticularis such that it activates the G protein, leading to the activation of adenylyl cyclase (which produces cAMP from ATP.)
cAMP activates PKA, responsible for phosphorylation of transcription factors in the cell, such that these transcription factors activate the transcription of the StAR mRNA.
StAR protein will be translated by ribosomes, such that it then goes to the mitochondrial membrane where it is activated by PKA phosphorylation. This allows cholesterol to go into the mitochondrial membrane, so the cytochrome P450 side chain cleavage enzyme is able to act on cholesterol and form 5-pregnenolone.
5 pregnenolone is able to exit the mitochondria and get further processed and leading to the formation of testosterone/estradiol.
ACTH increases the amount and activity of LDL receptors, such that storages of cholesterol can increase in the cells through LDLs, converting into HDLs.
What hormone stimulates the production of testosterone/estradiol from the testis/ovaries? Explain the synthesis pathway for these hormones.
Luteinizing hormone (LH) is responsible for stimulation.
LH binds to its receptor and activates adenylyl cyclase leading to an increase in cAMP (and PKA activation.)
PKA is then going to activate specific transcription factors which code for the StAR mRNA. StAR mRNA will then be translated by ribosomes, such that the steroid acute regulatory protein is able to go to the mitochondrial membrane, get phosphorylated (activated) by PKA, and then allow cholesterol to enter through.
In the mitochondrial matrix, cholesterol is going to be acted upon by cytochrome P450 SCC, leading to the development of 5-pregnenolone, which can exit the mitochondrial matrix into the cytosol, go to the smooth endoplasmic reticulum, and get processed to become testosterone or estradiol.
The leydig cells make up ?% of the testis, whereas the seminiferous tubules make up ?% of the testis. Which cell is responsible for the production of sperm cells? What about testosterone?
Leydig cells: 5%
Seminiferous tubules: 80%
Leydig cells are responsible for the production of testosterone, whereas the Sertoli cells are responsible for supporting sperm development.
Where are the testis located in mammals and why is this the case?
In mammals, the testis are located outside the abdominal cavity in the scrotal sac. The body is too hot for sperm cells to develop properly, so they must be outside.
What hormone stimulates the secretion of follicle stimulating hormone and luteinizing hormone from the anterior pituitary?
How is this hormone stimulated to be secreted? What do FSH and LH do in males? How is synthesis of these hormone inhibited?
Gonadotropin releasing hormone stimulates secretion of FSH and LH from the anterior pituitary.
GnRH is stimulated to be secreted from the hypothalamus by Kisspeptin.
Kiss-1 gene (which produces kisspeptin) will activate GnRH releasing neurons which will initiate the process of development of GnRH.
When FSH and LH go into circulation, they are going to be responsible for acting on the Leydig cells to stimulate testosterone production and act on the Sertoli cells in the seminiferous tubules to assist in development of sperm cells.
When FSH acts on the Sertoli cells, it will also stimulate the production of a hormone called inhibin B, inhibiting the secretion of FSH from the anterior pituitary.
The testosterone produced will go towards spermatogenesis, towards the development of secondary sex characteristics and growth. After this testosterone will have a negative feedback on both the anterior pituitary and hypothalamus, inhibiting LH and GnRH. Testosterone will act as negative feedback inhibitor for KNDy neurons to inhibit the secretion of Kisspeptin.
What stimulates the activation of gonadotropin releasing hormone (GnRH) neurons, such that GnRH is produced and secreted? At what point in your life does this process start?
Kisspeptin stimulates the activation of gonadotropin. When puberty begins GnRH hypothalamic neurons will begin producing receptors for kisspeptin and kisspeptin hormone, leading to activation of the GnRH hypothalamic neurons. This leads to the production of GnRH to produce and secrete FSH and LH. This altogether, leads to the surge in testosterone for men.
1) Where was the kiss-1 gene originally identified?
2) What happens as a result of loss-of-function mutations in the Kiss-1 gene?
3) What does Kiss-1 gene lead to the production of, and what are its roles?
1) Kiss-1 was originally a tumor suppressor gene active against metastasis of melanoma and breast cancer.
2) As a result of loss-of-function mutations in the Kiss-1 gene, this will prevent individuals/animals from entering puberty. This will also make these individuals infertile as well. Therefore this gene is important for human reproduction, and it has to turn on at a specific time in your life.
3) Kiss-1 gene leads to the production of kisspeptin, produced by hypothalamic nuclei (from KNDy neurons.) These neurons synapse onto GnRH producing neurons and secrete Kisspeptin, which bind to Kiss-1 receptors on GnRH producing neurons. As a result, these Kiss-1 and KNDy neurons are able to integrate a bunch of peripheral and central signals to control the secretion of GnRH from the producing neurons in the hypothalamus.
What are the roles of androgens in males?
- spermatogenesis in the seminiferous tubules
- growth and maintenance of the male reproductive system (epididymis, vas deferens, seminal vesicles, prostate gland, penis) everything requires for sperm maturation, nutrition, and transport
- maintenance and development of secondary sex characteristics, like muscle growth and facial hair
- behavioral effects (high concentrations of testosterone = aggression)
Surges in testosterone happen at specific times in the males (namely 6 months and 10-17 y/o)
Why are these surges important?
Early development of the fetus and puberty (important for development of different male characteristics)
The XY genotype leads to development of what sex hormone and development of what human sex? What about the XX genotype?
Genetically, XY should lead to a phenotypic male. The testis will lead to a huge production of androgens.
XX should lead to a phenotypic female. Development of the ovaries will lead to production of estrogen.
What is the difference between tonic and cyclic regulation of hormone secretion?
Tonic hormone regulation means that the levels do not cycle (usually the androgen concentrations are pretty constant)
Cyclic hormone regulation that hormones will be regulated throughout the month. At specific points during the month, there will be higher concentrations of estrogen, and at other, there will be lower concentrations.
How is it that males and females sex is dictated during pregnancy?
Very early on pregnancy, XX and XY are going to dictate the development of a male vs female fetus.
Males: The embryo develops a bipotential gonad. In embryos with XY chromosomes, the SRY gene will be present, leading to the development of testis from the bipotential gonad. Sertoli cells begin to release the anti-Mullerian hormone, shrinking the Mullerian Duct. As a result of the SRY genes and Sertoli cell formation, this will end up leading to the formation of more Sertoli cells (Leydig cells) and production of testosterone and dihydrotestosterone.
This allows for the Wolffian duct to prevail, leading to the formation of the development of vas deferens and epididymis. This is all due to the presence of the SRY gene on the Y chromosome.
Females: They also form the bipotential gonad as well. They don’t produce the SRY gene because of no Y chromosome. It just continues to differentiate into the ovaries. Because Sertoli cells are no produced, the Wolffian duct will diminish and the Mullerian duct will prevail.
What specific transcription factors enable the development of the testis? What about the ovaries?
Males: The embryo first has to have XY chromosomes. If this is the case, the embryo will then lead to the activation of a specific transcription factor known as SOX-9. This is activated by the SRY gene, by prostaglandin D synthase and fibroblast growth factor 9. Activation of SOX-9 leads to the development of the testis.
Females: In XX embryos, SOX-9 has to be inhibited. In XY embryos, there’s something called the Wnt4/beta-catenin pathway that shuts off SOX-9 production. BUT as long as SOX-9 is not present, this can then lead to ovary development.
Explain how Congenital Adrenal Hyperplasia can lead to issues with sexual differentiation, and give examples of different types.
CAH: adrenals do not produce enough glucocorticoids (like cortisol) and other steroids like aldosterone as a result of a mutation in a specific enzyme for steroid hormone synthesis that prevents these steroids from being synthesized.
1) Issue with 21-hydroxylase: issues with cortisol production. As a result, all of the things that are used to try and synthesized cortisol will not be able to do so, therefore, this will lead to too much androgen production. Because of this, lots of androgens will be produced from the adrenals, leading to virilization of female fetuses and early puberty for males.
2) Issues with the cytochrome P450 SCC: no androgens are produced. Since no androgens are produced, this can end up leading to feminization of male fetuses.
3) Issues with the enzymes responsible for converting dehydroepiandrosterone (DHEA) into testosterone: males do not produce enough testosterone and become feminized. Females have too much DHEA circulating and DHEA will bind to the androgen receptors which will end up leading to the masculinization of females.
Explain how a deficiency in 5alpha-reductase can lead to issues with sexual differentiation.
5alpha-reductase deficiency: responsible for converting testosterone into 5alpha-dihydrotestosterone (DHT.) DHT is required for external male genitalia development. Therefore, if there is a deficiency in 5alpha-reductase, the development of the external male genitalia will not occur. If there is a complete block of DHT production, the biological male (XY) will present externally as male.
In general, what can lead to issues with proper sexual differentiation of males and females?
Mutations or genetic issues that lead to discrepancies in the hormones produced or even the presence or function of specific receptors for these hormones
- ex. androgens might be produced but if there’s no receptors, it can lead to sexual differentiation.
- low androgen production in genetic male or defect in androgen receptor, this can lead to feminization of the male (presenting as female but genetically male)
- if androgen production occurs for females, they will present as male but genetically female.
When do humans have their growth spurt?
prior to and overlapping with the onset of puberty
Prior to the onset of puberty, what prevents the secretion of gonadotropin releasing hormone (GnRH)?
When puberty occurs, what allows the GnRH neurons to finally produce/secrete GnRH?
What is GnRH important for?
GABA neurons prevent GnRH neurons from releasing GnRH.
When puberty hits, this causes the KNDy neurons to turn on, secreting Kisspeptin. GnRH neurons will express receptors for kisspeptin and allows kisspeptin to bind to the Kiss-1 receptors on the GnRH neurons, allowing the GnRH neurons to become active.
As a result of GnRH secretion from these GnRH neurons, this will stimulate the anterior pituitary to begin the synthesis/production of luteinizing hormone and follicle stimulating hormone in both males and females.
As a result of both testosterone and estrogen, what changes do males go through during puberty?
Puberty as a result of testosterone/androgens:
- changes in hair texture and distribution
- changes in sebaceous glands in the skin (acne)
- increases in muscle mass
- growth of larynx (voice deepens)
- growth of external genitalia, prostate, and seminal vesicles
Puberty as a result of estrogen:
- linear bone growth
As a result of androgens, follicle stimulating hormone, estrogen, prolactin, and progesterone, what changes do females go through during puberty?
- development of pubic hair and changes of sebaceous glands of the skin (androgens)
= linear bone growth and growth plate closure (androgens and estrogens) - uterine growth and development (estrogen and progesterone)
- breast development (estrogen, progesterone, and prolactin)
- ovarian follicle maturation (estrogen and follicle stimulating hormone)
!! ovulation starts !!
What is delayed puberty and the causes? What is precocious puberty and the causes?
Explain the difference between isosexual and contrasexual precocious puberty.
Delayed puberty: no signs of puberty by 13 for females and 14 for males
- causes: problems with hypothalamus and the pituitary or gonads
Precocious puberty: the appearance of secondary sexual development before age 6-7 in females and 9 in males
- causes: genetic issues, different hyperplasia or different types of cancers
Isosexual precocious puberty: individuals will go through puberty consistent with their phenotypical sex
contrasexual precocious puberty, they go through puberty early but the secondary sexual development they go through aren’t consistent with their biological sex
