LECTURE 24 - puberty and sex differentiation Flashcards
What is the gonads?
The organ that produces gametes - ovary or testes
What are gametes?
Mature male or female reproductive cell with a haploid set of chromosomes (gametogenesis)
Female = oocyte (egg - produced by oogenesis)
Male = spermatozoa (sperm - produced by spermatogenesis)
Germ cell = sperm or oocyte or their developmental precursors
What are primordial germ cells?
- male and female embryos are indifferent until week 7
- diploid germ cell precursors
- arise during gastrulation ~ week 3
- epiblast derived
- during weeks 3-7
- proliferate by mitosis
- migrate by amoeboid movement to region of Doral wall that will form the gonads (gonadal ridges)
- migration is guided by chemotaxis
What happens to PGCs from week 7 onwards?
- can now differentiate between male and female
- the Y chromosome is unable to encode enough to form a testis
- instead the Y chromosome encodes a controller gene = testis determining factor
What is SRY?
Sex-determining Region Y gene = Testis Determining Factor (TDF)
- discovered to be conserved across mammals
- female mice with SRY transgene show male development
- XY females have SRY mutations or deletions and XX males have SRY translocations
- SRY is a transcription factor - controller gene
How do testes develop from week 7 onwards?
3 sets of cells that start to arrive at gonadal ridges
- columns of cells from coelomic epithelium - proliferate and penetrate deeply to from primitive sex cords - express SRY –> sertoli cells
- PGCs arrive, become associated with primitive sex cords, sex cord cells surround PGCs and form seminiferous tubules (basic structural unit)
- migratory cells from mesonephric primordial (form the vascular system of testes) and form Leydig cells
Describe the structure of the testes
WITHIN seminiferous tubules
- prospermatogonia
- sex cord cells form Sertoli cells
BETWEEN seminiferous tubules
- vascularisation and clusters of Leydig cells form
- SRY no longer expressed; testes produce hormones => development of male reproductive system
How are the ovaries formed?
- sex cords do not penetrate deeply, they cluster around PGC (oogonia) => primordial follicles –> form somatic cell type called granulosa
- mesonephric cells - form vasculature and thecal cells (second important cell type)
- there is no endocrine activity from the fetal ovary during development of the female reproductive system
- further development is dependent on the presence of normal germ cells
What is Turner’s Syndrome?
- genetically XO (only has e1 X chromosome)
- normal oocyte development requires both X chromosomes –> oocyte death
- normal ovary development requires normal germ cells –> ovarian dysgenesis
How does the internal reproductive system develop from weeks 8-12?
- gonads formed from bipotent structure
- internal reproductive formed from 2 separate unipotent structures
Wolffian duct = male
Mullerian duct = female
How is the male internal reproductive system formed?
- testis produces androgens (Leydig) that maintain Wolffian ducts
- testis also produce Mullerian Inhibitory Substance (MIS) aka Anti-Mullerian Hormone (AMH) that causes regression of Mullerian ducts (produced by Sertoli cells)
Females follow default pathway
How do male external genitalia form?
- androgens and dihydrotestosterone (DHT) produced from fetal testes to promote male development
- testosterone –> dihydrotestosterone by enzyme called 5alpha-reductase
- genital tubercle –> penis
- uro-genital fold –> spongy urethra
- labio-scrotal swelling –> scrotal sac
How do female external genitalia develop?
- female development = default pathway
- if androgens are not produced female genitalia develop
- genital tubercle –> clitoris
- labio-scrotal swelling –> labia majora
- uro-genital fold –> labia minora
What is puberty defined as?
- menarche (female) at ~12.9yrs
- first ejaculation (male) at ~13.4yrs
- activation of the HPG axis
- secondary sexual characteristics
- growth spurt
- reproductive maturity
What is the gonadotrophin releasing hormone (GnRH)?
- peptide hormone produced by hypothalamus
- produced from 92 aa prepropeptide
- stimulates the release of gonadotrophins from anterior pituitary
- at puberty, gonadal activation is triggered by activation of pulsatile GnRH secretion
- continuous GnRH leads to down regulation of gnRH receptor on surface of gonadotroph cells - no stimulation of FSH/LH release
What is the GnRH pulse generator?
- 54 aa neuropeptide transmitter - kisspeptin 1 (KISS1) binds to KISS1 receptor (aka GRP54)
- kisspeptin-expressing neurones are intimately associated with GnRH-secreting neurones
- kisspeptin pulses match GnRH pulses
- kisspeptin expression rises at puberty
- exogenous kisspeptin administration induced puberty
How is there indirect communication from the hypothalamus to the anterior pituitary?
- indirect communication through blood system
- GnRH secreted into capillaries in the primary portal plexus
- transport GnRH into anterior
- binds to GnRHR on gonadotroph cells within anterior
- produce FSH and LH and released into blood system where it can be transported to ovary and testis
What are the gonadotrophins?
- HPG axis: FSH and LH
- hCG
- glycoproteins
- binds receptors on cell surface and signal via G-proteins
What is Luteinising Hormone (LH)?
Secreted by: gonadotrophs (anterior pituitary)
Acts on: Leydig, theca and granulosa cells
Structure: common a-chain (116 aa), unique B-chain (121 aa), 1 carbohydrate chain
Receptor: LHCGR
What is follicle stimulating hormone (FSH)?
Secreted by: gonadotrophs (anterior pituitary)
Acts on: Sertoli and granulosa cells
Structure: common a-chain (116 aa), unique B-chain (111 aa), 2 carbohydrate chains
Receptor: FSHR
What is chorionic gonadotrophin (hCG)?
Secreted by: Trophoblast cells (embryo)
Acts on: luteal cells (corpus luteum)
Structure: common a-chain (116 aa), unique B-chain (145 aa), 2 carbohydrate chains
Receptor: LHCGR
What are sex steroids?
All derived from cholesterol (via acetate)
3 families
1. Progestagens - pregnancy (+placenta)
2. Androgens - maleness (+adrenals)
3. Oestrogens - femaleness (+liver, adrenals, adipose and placenta)
- lipid soluble - act via nuclear receptors, act via steroid response elements (SREs)
- bound to carrier proteins - often bound to albumin or sex hormone binding globulin (SHBG), in testis there is androgen binding protein (ABP)
What are the different progestagen forms?
- Progesterone (P4)
- 17a-hydroxyprogesterone (17a-OHP)
- 20a-hydroxyprogesterone (20a-OHP)
Receptors = PR-A and PR-B
What are the different androgen forms?
- 5a-dihyrodtestoterone (DHT)
- Testosterone (T)
- Androstenedione (A4)
- Dehydroepiandrosterone (DHEA)
Receptor = AR
What are the different oestrogen forms?
- Oestradiol 17B (E2) (puberty to menopause)
- Oestriol (E3) (pregnancy)
- Oestrone (E1) (post-menopause)
Receptors = Era and ERB (alpha and beta)
What does potency depend on?
- how well steroid fits binding site on receptor
- varies within each class
- some bind receptor from other classes e.g. synthetic progestagens in contraceptive pill can be androgenic
- some bind but don’t activate e.g. act as antagonists e.g. Mifepristone (RU486) - anti-progestagen (abortion pill)
What are secondary sexual characteristics (SCC)?
Timing varies but sequence the same (Tanner staging)
Girls
- ovarian estrogens => growth of breasts and genitalia
- ovarian and adrenal androgens => pubic and axillary hair
Boys
- testicular androgens => growth of pubic, facial and axillary hair, genitalia, enlargement of larynx and laryngeal muscles, lengthening and thickening of vocal cords
What is a growth spurt?
- girls grow about 25cm, boys about 28cm
- boys begin 2 years later - height at take off is ~10cm greater
- average growth spurt lasts 24-36 months
How does a growth spurt occur?
- during development, cartilage becomes ossified except for a small region of cartilage at each end, the epiphyseal growth plate
- the key endocrine regulator of postnatal growth is growth hormone (GH) from the anterior pituitary
How does GH promote growth development?
- GH stimulates production of insulin-like growth factor-1 (IGF-1)
- IGF-1 directly simulates chondrocyte cell division and bone growth
- IGF-1 is produced by the liver and locally by chondrocytes in the growth plate - endocrine and paracrine
- in early stages of puberty, low levels of oestrogen, stimulates GH-IGF-1 axis and androgens stimulate chondrocyte activity
- later puberty (high levels of oestrogen) causes fusion of epiphyseal growth plates
- cartilage entirely replaced with bone- statuary growth ceases
Describe the timings of puberty?
- research based mainly on females
- some genetic impact, African and Hispanic descent tend to start earlier, also similar to family
- environmental influences: endocrine disruptors
- age at menarche has decreased from ~17yrs in 1840s to ~13yrs by 1950s
- weight at menarche has remained constant ~47kg for females
What is Leptin?
- produced by white adipocytes
- patients with mutations in obsession or LepR gene fail to enter puberty
- Leptin receptors are in hypothalamus
- involved in puberty
- unsure if it is trigger or permissive
