Lecture 37 Flashcards
What are the two categories of somatic cells?
- Sustaining cells
- Endocrine cells
What are the two kinds of sustaining cells and their karyotypes?
- Granulosa Cells (XX)
- Sertoli Cells (XY)
What are the two kinds of endocrine cells and their karyotypes?
- Theca Cells (XX)
- Leydig Cells (XY)
What are the two kinds of germ cells, their haploid variations, and the karyotypes of both?
- Ooogonia (XX); Ova (X)
- Spermatogonia (XY); Sperm (X or Y)
What is the process of the hypothalamo-pituitary-gonadal axis?
- Kisspeptin from the brain signals the hypothalamus to release GnRH
- GnRH enters anterior pituitary and releases FSH and LH , which enters the gonads
What feedback occurs throughout the hypothalamo-pituitary-gonadal axis?
- Inhibin from granulosa cells inhibit FSH
- Progesterone and androgen from Leydig cells inhibit every aspect of the axis.
- Estrogen from Leydig cells both inhibit and promote aspects of the hypothalamo-pituitary-gonadal axis
- Inhibin from the sertoli cells inhibits the entirety of the axis
When is meiosis completed?
- Male: release of sperm
- Female: upon fertilization, the oocyte is allowed to complete meiosis
Please provide the process of creating sperm.
- Spermatogonia undergo mitosis until meiosis begins (mainly happens as an embryo but also as a reproductive adult)
- Before the first meiotic division, known as primary spermatocyte
- After the first meiotic division, known as secondary spermatocyte
- After second meiotic division the cells are known as spermatids that develop into sperm
Please provide the process of creating eggs
- Oogonia undergo mitosis until meiosis begins
- Before the first meiotic division, known as primary oocyte
- After first meiotic division split into first polar body and secondary oocyte (this only happens once adulthood is reached)
- Secondary oocyte is then ready for ovulation and first polar body disintegrates
What occurs during fertilization?
The sperm meets the egg, which then undergoes the second meiotic division at that point, where the second polar body disintegrates. A zygote is then formed.
What are the three sources that the gonads and internal reproductive tract develop from?
- mesothelium (coelomic epithelium) lining the posterior abdominal wall
- Underlying mesenchyme (intermediate mesoderm)
- Primordial germ cells
How does the mesothelium differentiate into gonads?
- Forms the primordium of future gonads (genital or gonadal ridge) - a bulge of tissue medial to the mesonephros (temporary kidney).
- Primary sex cords penetrate the mesenchyme
- Indifferent gonad consists of a medulla and a cortex
- XX embryo causes ovary to originate from cortex and medulla declines
- XY embryo causes the medulla to develop into testis and the cortex regresses
How does the intermediate mesoderm (mesenchyme) differentiate?
- Gives rise to the nephrogenic cord, which gives rise to the pronephros, mesonephros and metanephros
- Mesonephroi gives rise to components of the internal reproductive tract and of the urinary system (Mesonephric/Wolffian ducts develop in the 4th week and the Paramesonephric/mullerian ducts in the 6th week)
How does the primordial germ cells (PGC) differentiate?
- Give rise to gametes which are differentiated from somatic cells very early and emigrate from the ectoderm (3rd week) via the extraembryonic endoderm (5th week) into the primordium of future gonads, the genital/gonadal ridge
- Through an interaction with coelomic epithelial cells, the primordium for the testis evolves in the seventh week if a Y chromosome is present or for the ovary in the 8th week if absent
How do genital ridges typically appear?
Longitudinal outgrowths along the surfaces of the mesonephroi within the coelomic cavity.
What happens when PGCs colonize the genital ridges?
After leaving the hindgut via the dorsal mesentary, PGCs colonize the genital ridges.
- The ridges are bipotential and through an interaction with the coelomic epithelial cells, can differentiate into testes or ovaries
What genes are expressed for XY individuals during differentiation?
- Sry expressed in XY genital ridges
- Initiates Sox9 expression and testis differentiation
What genes are expressed for XX individuals during differentation?
- Absence of Sry in genital ridges
- Rspo1 and Wnt4 initiate ovary differentiation
Which genes, if deleted, are sufficient to induce transdifferentiation of gonads in adult mice?
- Dmrt1 in the testis
- Foxl2 in the ovary
What theory does the existance of transdifferentiation suggest?
Development of the opposite sex is actively repressed throughout life
What is the process of sex maintenance during the fetal develpment stage?
- Male: Sry -> Sox9 -> Fgf9 and Ptgds -> Sox9
- Female: Wnt4 and Rspo1 -> B-catenin
What is expressed during the postnatal development stage for sex maintenance?
- Male: Sertoli cells express Dmrt1
- Female: Granulosa cells express FoxI2
Describe the case of the two Italian families:
The gene for R-spondin1 (RSPO1 protein, Rspo1 gene) is mutated leading to female-to-male (XX) sex reversal
What is the cloaca?
The blind end of the caudal hindgut forms the cloaca, which is separated from the outside by the cloacal (urogenital) membrane.
How does the cloaca divide into urogenital sinus and rectum?
- A septum grows downward at 4 weeks of gestation, separating the cloaca into a posterior compartment, which will become the rectum, and an anterior compartment which forms the urogenital sinus
What does the urogenital sinus develop into?
The urinary and reproductive organs
What does the intermediate mesoderm develop into?
The nephrogenic cord
What does the nephrogenic cord develop into?
- Pronephros (cranial segments)
- Mesonephros (intermediate segments)
- Metanephros (caudal segments)
What do the pronephros and mesnephros become?
They are temporary excretory organs
What does the metanephros become in mammals?
The permanent kidney
At week 4, what do the differentiated nephros form?
- Pronephros degenerates
- Mesonephros begins to develop into a cup-like outgrowth into which capillaries push to form a primitive glomerulus, which the ureteral bud grows out of
- Metanephros begins as the ureteral bud grows
What internal genital organs are developed by week 7th?
Both sexes on both sides consist of two canal systems: mesonephric (Wolffian) and paramesonephric (Mullerian) ducts.
What happens before sexual differentiation is detectable?
A genital (phallic) tubercle and two genital (future scrotal or labial) swellings appear around the cloacal membrane.
When are sexual organs detectable by?
Week 12
Which of the duct systems develop on the presence or absence of functional fetal testes?
The male Wolffian (mesonephric) duct, because of the testosterone release from the testes.
Why doesn’t the Mullerian (paramesonephric) duct form in males with functional fetal testes?
The testes secrete Anti-Mullerian Hormone (AMH) which degrade the Mullerian Hormone.
What is the process of the differentiation of the testis?
- In the genetic male SRY expresses in the urogenital ridge cells and triggers differentation of testes during the 7th week.
- Fetal Sertoli cells secrete AMH (aka Mullerian Inhibiting Substance (MIS))
- Fetal Leydig cells secrete insulin-like peptide 3 (INSL3) and testosterone (T)
What does testosterone turn into inside the Leydig cells?
The 5a-reductase present in target tissues converts T into dihydrotestosterone (DHT)
How does the prostate develop?
It develops in tissue of the posterior wall of the urogenital sinus and surrounds the prostatic urethra at the base of the urinary bladder
How does the penis form?
Signals from the cloaca initiate penis formation, wth the origin of cells destined to become the penis differing between species.
What does estrogen do to the nephrotic ducts?
It increases the development of the Mullerian duct, the vaginal vestibule, the labia and the Clitoris
What does DHT do in male reproductive development?
Increases the development of prostate, scrotum and penis.
What does Wnt signaling essential for in reproductive development?
Mullerian duct development, differentiation and regression
What is chicken ovalbumin upstream promoter transcription factor 2 (COUP-TF2)?
It is a nuclear receptor that is essential in many tissues and has been identified in the development (elimination) of the Wolffian duct.
Is the default setting for mammalian sexual characteristics female?
No, female ducts must be actively retained and male ducts need to be actively elimintated via COUP-TF2.
What happens if COUP-TF2 is absent in an XX organism?
Both the Mullerian and Wolffian ducts are present but the Wolffian duct is underdeveloped. No difference in XY. This could lead to human sexual disorders, specifically in females.
When does external genitalia differentiate during gestation?
Between week 7 and week 12.
How does the urogenital sinus develop into the externl genitalia?
- Prostate gland develops
- Genital tubercle (which eventually forms into primordial phallus) develops around 4th week and by 9th week becauses recognizable as a penis or clitoris
- Male with DHT: penis (urethral closure), scrotum and prostate
- Female without T: development of a perineal urethra, uterus, clitoris and vagina
What is required in the development of the penis and prepuce?
Normal and hypospadic development involves epithelial (ectoderm, endoderm and mesoderm fusion events)
What is hypospadias?
A birth defect that occurs when the opening of the urethra is not in the typical location on the penis (lower down on penis).
What is epispadias?
A birth defect that occurs when the opening of the urethra is not in the typical location on the penis or below the penis.
What are the four locations for hypospadias in order from distal to proximal?
- Glandular (below glans penis)
- Penile (on penis)
- Penoscrotal (between penis and scrotum)
- Perineal (below the scrotum)
What are the three phases of testicular descent?
- Abdominal Translocation
- Transinguinal Migration
- Inguinoscrotal Migration
What is abdominal translocation?
The gubernaculum anchors the tesis at the distal end, gradually expands and invades into abdominal musculature until the testis is positioned near internal inguinal ring
What is Insl3?
- It is a member of the insulin-relaxin family of peptides that act through a G-protein coupled receptor relaxin/insulin-like family peptide receptor 2 (RXFP2)
- INSL3 production starts in rodent and human fetal Leydig cells around the same stage of development and appears to be autonomous and stimulates growth of gubernaculum
What is Transinguinal Migration?
- The gubernacular bulb enlarges greatly, dilating the inguinal canal allowing passage of testis and epididymis.
- Deficits associated with either Insl3 or testosterone have not been documented
What is inguinoscrotal migration?
The gubernacular bulb continues to grow towards the bottom of the scrotum and over time regresses to attach the vaginal tunic to the scrotal wall
What is testosterone required for in inguinoscrotal migration?
It is require to masculinize structures that are involved in this phase
- Testosterone exerts a negative action on the cephalic ligament facilitating its gradual regression
- Positive action on masculizing the genitofemoral nerve (GFN - sexually dimorphic, with androgen receptors in the cell body)
What is released from the GFN?
Calcitonin gene-related peptide to proved directional guidance to the gubernaculum during inguinoscrotal migration.
What is testicular torsion?
- Failure of normal posterior anchoring of the gubernaculum, epidydimis and testis “bell clapper deformity” which leads to weaker connective tissue and ligaments and can occur in utero or later in life.
- The torsion occurs when the spermatic cord twists and the venous drainage obstructs leading to necrosis and infarction (process leading to necrotic tissue caused by loss of adequate blood supply)
What is cryptorchidism?
Undescended/Ectopic testes
What does not occur in cryptorchid patients?
- Spermatogenesis
- Lower levels of testosterone from Leydig cells
What are the two types of cryptorchidism and their commonality?
- Isolated (85%)
- Syndromic (15%)
What are the two types of isolated cryptorchidism?
- Congenital
- Acquired
How can syndromic cryptorchidism occur?
- Caused by hypothalamic and pituitary abnormalities (Ex. Kallman syndrome), isolated hypogonadotropic hypogonadism, and Prader-Willi syndrome
- Disorders of testicular testosterone secretion (Ex. Klinefelter’s syndrome), testicular dysgenesis syndrome, Noonan syndrome and congenital adrenal hyperplasia due to 3B-HSD deficiency
- Disorders of testosterone action (Ex. androgen insensitivity syndrome)
- Congenital disorders that lead to poor development of abdominal musculature and lack of muscle tension, such as gastroschisis, opmphalocele, bladder exstrophy and prune belly syndrome
Where are the 5 places (in order from superior to inferior) that testes can sit (with or without cryptorchidism)?
- Nonpalpable
- Inguinal
- Suprascrotal
- High scrotal
- Scrotal
When should testicular descent be finished?
Before birth in humans
What can cryptorchidism lead to?
An increased risk of testicular cancer and infertility in adult life
What two Leydig cell hormones are required in testicular descent?
- Testosterone
- Insulin-like peptide 3
What is the most common cause of isolated cryptorchidism?
A pathogenic intrauterine environment
What is the order of sexual differentiation?
- Chromosomal sex at fertilization
- Indifferent Gonadal sex at zygote stage
- Development of sex organs
- Endocrinium brain
What masculinizes the brain in the male fetus?
Testosterone synthesized by the fetal testis diffuses into brain and gets aromatized into estradiol
What protects the brain from the effect of circulating estrogens from the mother?
- Alpha-fetoprotein which binds strongly to estrogens but not to T
What in the brain is larger in ale rats than female?
Sexually dimorphic nucleus (SDN) in the preoptic area
What happens to the SDN in females injected with T?
The SDN grows larger than in normal females
What does large SDNs lead to in terms of behavior?
Mounting
What found in breast-fed 3-month-old infants serum leads to negative correlation with T?
The phthalate monoester, monobutyl phthalate (mBP)
Describe the correlation of diethylhexyl phthalate (DEHP)
The metabolites in the first trimester maternal urine samples are inversely associated with anogenital distance (AGD) in male, but not female, newborns.
