Sexual differentiation, Reproductive hormones and gametogenesis Flashcards
What is the sex cascade?
Genetic sex
Gonadal sex
Somatic sex
Brain sex
Define sex
The process by which a genetically novel individual is formed as the result of mixing of genes from two or more individuals
Why do we need sex?
Recombination and allelic assortment helps to generate variation in populations that allows adaptation to changing selective pressure
Name a species where the female is heterogametic
Chickens - ZW system
What determines gonadal sex?
Genetic sex of indifferent gonad via paracrine peptide hormones and small endocrine molecules around the body
XO
Turner’s syndrome
Ovary
XXY
Kleinfelter’s syndrome
Testis
XXSxr
X-Y translocation
Testis
XY/
Deletion of part of Y
Ovary
Describe X inactivation
All but one X inactivated to prevent OD of genes carried on X
Lyonisation to produce Barr bodies
Done on a random basis amongst cells in epiblast at the primitive streak stage
What is the key gene determining the effect of the Y chromosome?
SRY
Sex determining region of y
Describe SRY
Size
Effector region
Effects
223 aa
Highly conserved DNA binding domain of 79 aa called an HMG box (high mobility group of proteins)
HMG box binds both DNA and RNA, affecting their accessibility and stability
Affects expression of a number of other genes e.g. SOX9 involved in gonad differentiation
Describe formation of the genital ridges
W5 and 6
Colonised by primordial germ cells migrating from extraembryonic mesoderm to caudal part of the yolk sac and then onto the dorsal mesentery and upwards to genital ridges
Ridges run parallel either side of gut
Coelomic epithelium proliferates to form primitive sex cords
Initially bipotential with both sets of ducts
How did the Y chromosome develop?
Acquisition of a male-determining gene to form a proto-Y chromosome
Further acquisition of antagonistic mutations, aided by a series of inversions suppresses opportunities for recombination
Lack of recombination leads to accumulation of repetitive sequences
How do germ cells form in humans?
Differentiate from amniotic ectoderm under influence of BMP4 produced in autocrine fashion by amnion and WNT3A from overlying cytotrophoblast
Name the TFs produced by the amnion
OCT4
NANOG
SOX2
What is the embryo called when it is bipotential with respect to gonads?
Indifferent gonad stage
What happens when primitive germ cells arrive at the genital ridges in females?
Female: No SRY. Default pathway.
Coelomic epithelium proliferates to form cortical sex cords. Stromal cells from cortical cords surround oogonia to form primary follicles.
Paramesonephric ducts grow due to lack of MIS, fusing together inferiorly and with the urogenital sinus to form the Fallopian tubes, uterus and top of vagina.
Mesonephric ducts degenerate due to lack of androgens.
What happens when primordial germ cells reach the genital ridge in males?
Male: SRY switched on in coelomic epithelial cells of sex cord (Sertoli cells), which proliferate to form seminiferous tubules.
SRY switched on in stromal cells (Leydig cells) which start to produce androgens.
Androgens maintain the mesonephric duct
Sertoli cells make MIS Mullerian Inhibitory Substance that makes the paramesonephric ducts degenerate.
What are the messengers released by the testis to mediate somatic sex?
- Androgens –> penis, scrotum, vasa, accessory sex glands
Testosterone processed by 5 alpha reductase present in local tissues, produces dihydrotestosterone DHT, which drives differentiation of external genitalia. - Insulin-like hormone 3 –> gubernaculum contraction –> testis descent
- MIS –> uterine primordium regresses in males
What is it called when genetic and gonadal sex males develop female genitalia? What causes it?
Guevadoces Lack 5alpha reductase Cannot make DHT At puberty extreme virilisation as testosterone levels rise Urethra continues to open near anus
How does female somatic sex develop?
Absence of androgens results in lack of closure of urogenital folds.
What is the difference between male and female brains?
- Structural - sizes
- Chemical - transmitter levels
- Physiological - metabolism, cyclicity
- Psychological - gender, aggression
- Cognitive - verbal fluency, spatial ability
How can you artificially masculinise a brain? What does that tell us?
Administer testosterone to females within first few days of birth
Suppresses hypothalamic cyclicity and oestrous cycles
Suggests androgen exposure via hypothalamus determines ‘brain sex’
Discuss primary hermaphroditism
Anomalies of gonad
- Ovary on one side, testis on other. Caused by v early loss of Sry in a cell that contributes to one half of the embryo
- Mixed ovarian testicular tissue in one or both gonads (partial or mixed gonadal dysgenesis) - often seen where sex chromosome mosaicism exists .
Discuss secondary hermaphroditism
Anomalies of soma
1. Testicular feminisation/androgen insensitivity syndrome - testis + female soma. XY overtly normal female sexual appearance. Lack top of vagina, uterus etc as still have Mullerian inhibitory substance.
2. Congenital adrenohyperplasia or adrenogenital syndrome. XX.
Impaired cortisol secretion due to a CYP21A2 mutation and thus 21-hydroxylase deficiency–> ACTH levels rise due to impairment of negative feedback –> hyperplasia adrenal cortex –> cortisol precursors accumulate –> converted to androgens which cause in utero virilisation of affected female fetus’ genetalia.
3. Micropenis - poorly developed phallus
4. Hypospadias. Urethra opens in ventral penis or vagina
How do androgens act?
Diffuse into cell Bind to androgen receptor in cytoplasm Dissociates from HSPs Translate to nucleus Dimerises Binds to regulatory sequences in promoters of androgen responsive genes
Define gender assignement
How others relate to you at birth
Define gender identity
An internal state of being, how people think of themselves.
Define gender stereotype
The socially expected attributes of men and women
Discuss a highly gendered society
Traditional Judeo-Islamic-Christian societies
Discuss a society with a third gender
Gender liminal
Berdache in native NA
Hijra North India
Mahu Tahiti/Hawaii
Discuss a non-gendered society
Semai Malaysia
What is the evidence that gender is learnt?
2y: gender identity ID as male or female
2-3y: gender role established, know what is expected of them
5y: gender constancy. Realise gender fixed
After: Gender policing - enforce gendered behaviour in each other and marginalise transgressors
Define gender variance
The predisposition to develop a gender identity that is not typically associated with the assigned sex
Define sexuality
The part of the emotional and intellectual make up concerned with the erotic
Define sexual identity
An internal state of being how one thinks of themselves, in terms of being attracted to members of the same or other sex.
Define sexual stereotype
The attributes socially expected of someone with a certain sexual identity
Is sexuality learned or inherited?
Evidence for inherited:
- Familial and twin studies suggest genetic influences
- Androgen exposure/CAH generates ‘tomboy’ like behaviour in XX girls. Increase in homosexual/bisexual behaviour reported.
Learnt:
- Evidence for associative learning during childhood between stimuli and sexual arousal
Summary: complex interplay between learning and inheritance
Define fecundity
Potential for reproduction - gamete production, fertilisation and carrying a pregnancy to term
Define fertility
The measure of reproductive outcome - the number of children born per person, couple or population
Define fertility rate
The number of births per time period per person/couple/population
Which factors affect fertility in women?
Fecundity Age (puberty/menopause) Episodic (monthly) Sub-fertility Other: Social convention e.g. nuns Choice (abstinence, contraception, abortion) Access to ART assisted reproduction technologies
Which factors affect fertility in males?
Fecundity: Age Continous Sub-fertility Other: Social convention Choice (abstinence, contraception) Access to ART
What is the male cessation of fecundity called? What is it due to?
Andropause
Due to loss of libido, erectile dysfunction, vascular pathology, nerve damage i.e. due to diabetes
Describe the menopause
Climacteric (fertility and sexual activity in decline) - onset of menopause 40 years onwards.
Ovarian decline and failure lead to secondary amenorrhoea (absence of menstruation)
When can premature menopause happen from? What proportion of women?
Twenties
2% women
How can you overcome menopause?
Donor egg/embryo transfer and hormonal priming can circumvent ovarian failure.
What leads to ovarian decline (and thus menopause)?
Fewer oocytes of lower quality –> chromosomal abnormalities
Follicular decline leads to hormonal changes and secondary amenorrhoea.
When do girls go into puberty wrt boys?
2 years earlier. Average age of puberty has been decreasing.
Which part of the pituitary gland regulates gametogenesis?
Anterior pituitary
What are the main regulators of gonadal function released from the hypothalamus/pituitary?
FSH
LH
Prolactin
What are the main regulators of gonadal function that provide feedback from the gonads?
Inhibin
Oestrogen
Testosterone
What secretes FSH and LH?
Gonadotroph cells in the anterior lobe of the pituitary gland
What secretes prolactin?
Lactotrophs in the anterior lobe of the pituitary gland
Histologically, which cells are basophilic and which are acidophilic in the ant pit?
Pink acidophilic = growth hormone or prolactin
Purple basophilic = TSH, ACTH, FSH, LH
How does GnRH get to the gonadotrophs?
Released by medial pre-optic and arcuate nucleus neurons in hypothalamus (integrates external ie photoperiod and internal ie emotional stimuli, travel via pituitary portal vein
How often does GnRH release peak?
Hourly
What does LH stimulate?
Thecal cells in ovary –> oestradiol
Leydig cells –> testosterone
Where do oestradiol and testosterone exert their negative feedback effects?
Gonadotrophs and GnRH neurons
What does FSH stimulate?
Granulosa cells + Sertoli cells –> inhibin
Where does inhibin exert its negative feedback effect?
Gonadotrophs
What does prolactin do?
Has very diverse and unlear functions Potentiates actions of LH and FSH through actions on receptors and enzymes e.g. 5 alpha reductase Enlargements of mammary glands Lactation Pulmonary surfactant fetal lungs Immune tolerance Fetal brain development
What regulates prolactin?
Negative action of dopamine released from TIDA neurons (dopamine in arcuate nucleus)
What does hyperprolactinaemia lead to? How do you treat it?
Both male and female infertility
Bromocriptine, D2 receptor agonist
How does the male reduce temperature in the testes?
Descent of testis into scrotum
Countercurrent heat exchange between testicular artery and pampiniform plexus of veins
Division of testis into compartments
What is the proper name for maldescent of the ovaries? What does it lead to?
Cryptorchidism
Teratocarcinoma, reduced spermatogenesis, subfertility
What is the structure of the testis?
Septa divide it into 250 lobules
Each lobule 1-4 seminiferous tubules
Total 600-1200 tubules (250m)
Tubules horse-shoe shaped. Both ends connect with rete testis –> efferent ductules.
How do released sperm move in rete testis and efferent ductules?
Bulk flow
Where do sperm mature?
Epididymis
When do seminiferous tubules develop and when do they activate?
Fetal period
Active at puberty
What is the epithelium of the seminiferous tubule like in the fetal period?
Not fully organised
No tight junctions between Sertoli cells
Spermatogonia not always on basement membrnae
What is the volume of the testis age 18?
Just under 20ml
Describe the structure of a seminiferous tubule
Going inwards Primordial germ cells/ spermatogonia/ spermatocytes/ spermatids
Sertoli cells make up wall (1 cell thick)
Basement membrane
Leydig cells outside
What enlarges in the testes at puberty and why?
FSH LH
Leydig cells and seminiferous tubules expand
What makes up the blood-testis barrier?
Blood and lymph confined to interstices and tight junctions between Sertoli cells are barrier
Compare and contrast the ovary and the testis
Germ cells in follicles/tubules
Germ cells called primordial oocytes/spermatogonial stem cells
Germ cells entering first meiotic division during fetal life then arrest in meiotic prophase (dictyate stage)/germ cells mitotic during fetal life then quiescent post-natally.
Most germ cells die around birth/survive to adulthood,
Relatively few oocytes left by puberty with potentially no stem cells/large population of renewable cells remains at puberty.
Compare and contrast generation of gametes in males and females
30 million sperm per day/1-2 oocytes each month
Spermatozoa released in testicular fluid, oocytes released in follicular fluid
Continuous output of androgens and inhibin/sequenced release of rising oestrogens –> oocyte release –> rising progesterone. Inhibin output rises pre oocyte release and remains high after it.
Continuous/cyclic
Describe the stages of spermatogenesis
- Mitotic proliferation. Spermatogonia from stem cells in basal compartment. 5-7 division rounds.
- Meosis. 1 and 2 spermatocyte - move from basal to apical compartment as they divide.
- Spermiogenesis/cytodifferentiation. Spermatid - haploid. Transform phenotype from round spermatid through elongating spermatid to
Spermatozoan. - Spermiation. Spermatozoa released luminally into testicular fluid in spermiation.
How come the basal compartment of the testes has a high testosterone conc?
Leydig cells secrete it in response to LH
Bound by androgen binding secreted by Sertoli cells in response to FSH
What are the two compartments of the testes and what divides them into that?
Tight junctions between sertoli cells divide into apical/adluminal and basal
What is the significance of the apical testicular compartment being an immunologically privileged site?
Spermatocytes undergo meiosis
Express foreign antigens due to formation of chiasmata
If tight junctions break down, can develop an autoimmune reaction and antispermatozoal antibodies, leading to subfertility
‘Autoallergic orchitis/alterations in tubular microenvironment’
How much androgen do Leydig cells produce?
4-10mg per day
What do Sertoli cells produce?
Inhibin and testicular fluid
Discuss the regulation of spermatogenesis
Sertoli cells Mitotic proliferation: FSH or testosterone Formation of primary spermatocyte? First meiotic division: testosterone Second meiotic division: testosterone Spermiogenesis: FSH Spermiation: LH Maybe oestradiol from Sertoli cells plays a role
How long is a spermatogenic cycle?
64 days
How is spermatogenesis timed?
Spermatogenic wave
Groups of stem cells within wedges of the tubule’s circumference initiate development at 16 day intervals. Locally groups of stem cells coordinate their time of entry into spermatogenesis, so the overall output of sperm is continuous but within different localities it is not synchronised.
Each step of spermiation takes a defined time, so only certain combinations of cell appearances seen
What is the cytoplasmic bridge?
During meiosis the cytoplasm doesn’t fully divide, allowing communication between X and Y haploid cells.
Describe spermatid maturation
- Form an acrosomal vesicle containing proteases that surround the nucleus
- Excess cytoplasm is packaged into the residual body which is phagocytosed by Sertoli cells
- Chromosomal condensation
- Replace histones with protamines
- Condensation –> loss of transcription in late spermatids and spermatozoa
- Cytoplasmic bridges finally separate and spermatozoa released
- Simultaneously developing flagellum
What is the effect of hypophysectomy on spermiation? How do you restore it?
Arrest in early meiosis
Nothing more mature than a primary spermatocyte seen
Lumen collapses as no fluid secretion from Sertoli cells
Restore needs both LH and FSH - the gonadotropins + inhibin
What makes up the acrosomal cap?
Proteases, hyaluronidase
What is in the neck of a sperm?
Centriole
What is the tail of a sperm made of?
Axial bundle of microtubules, axoneme (2 central singlets surrounded by 9 doublets). This is surrounded by 9 dense outer fibres which are non contractile, except for the end piece.
In mid-piece this combination is surrounded by helical mitochondria.
How is sperm transported out of the testes?
- Testis –> vasa efferentia–> epididymis. Passivley in bulk flow. Sperm non-fertile and immotile
- Epididymis –> vas deferens. 90% fluid reabsorbed so spermatocrit rises. Muscular contractions move the sperm along.
What happens in the epididymis?
Maturation and storage of spermatozoa
- Stiffening outer dense fibres in tail
- Addition of glycoproteins
- Change in lipid composition of membranes
- Testicular fluid reabsorbed 90% so spermatocrit rises
What is epididymal function based on?
Androgens
What causes low sperm count and what is the proper name?
Oligospermia
Cryptorchidism, overheating of testis (varicocoele), drugs (antimimotic, alcohol, xenobiotics, bisphenol A), hyperprolactinaemia, obstructive pathology f epididymis or vas e.g. congenital or post-infective
How many sperm normally produced per day?
30 million
List the whole testosterone synthesis pathway
Cholesterol Pregnolone Progestagens Testosterone 5alpha reductase to 5DHT
Functions of testosterone:
Stimulate accessory sex gland growth and secretion in men - seminal vesicle, prostate, epididymis
Stimulate secondary sex body hair patterns in men and women.
Exert anabolic and myotrophic effects to affect body shape
From about what age do testosterone concentrations start to fall?
Age 60 onwards
What is the structure of the gonadotrophins?
Glycoproteins with two peptide chains (92 aa + 2 carb groups)
LH has unique b chain of 122 aa + 2 carb groups
FSH has unique b chain of 111 aa 6 carb groups
What is the structure of inhibin?
2 peptide chains linked by disulphide bond
Where does inhibin go from Sertoli cells?
25% testicular lymph
Rest testicular fluid
What are the two phases of the ovarian cycle and how long do they last? What are the dominant hormones?
First 14 follicular phase. Rising oestrogen
Spike LH FSH
Second 14 days luteal phase, corpus luteum forming progesterone.
What are the two major cell types in the ovary?
Thecal and granulosa cells
What do thecal and granulosa cells do?
Thecal: secrete androgens under influence of LH
Granulosa: Convert androgens to oestrogen under influence of FSH
Oestrogen further stim the granulosa cells in positive feedback cycle
Granulosa cells also secrete inhibin - stim the thecal cells to secrete androgens, and stim granulosa cells to convert to oestrogen –> forms antral follicle
How does puberty affect thecal and granulosa cells?
Thecal cells of pre-antral follicle develop LH receptors, and granulosa cells develop FSH receptors
How do you form the pre-ovulatory follicle?
Granulosa cells form LH receptors, and under its influence start synthesising progesterone
LH also reactivates meosis, so oocyte moves on from first meiotic prophase to second meiotic metaphase
What is the action of oestrogen on the H-P axis?
Slowly rising: Reduces LH and FSH output
Hypothalamic arcuate nucleus = oestrogen reduces GnRH pulse amplitude.
Decrease in GnRH means gonadotrophic cells become hypersensitised to GnRH.
Also evidence that sensitivity of gonadotrophs changes intrinsically.
Rapidly rising: GnRH surges, hyperstimulates hypersensitised gonadotrophs to hypersecrete LH. Positive feedback. Triggers ovulation.
What is the action of LH in the ovary?
Thecal cells in ovary to release androgens
Granulosa cells - progesterone secretion. LH also reactivates meosis, so oocyte moves on from first meiotic prophase to second meiotic metaphase.
Make follicular surface thin and cause it to rupture at the stigma.
Why does oestrogen spiking not cause FSH to rise as much? Evidence?
Negative feedback effect of inhibin.
Antibody to inhibin during the late antral phase leads to much elevated FSH levels but has no effect on LH levels.
What changes histologically in the luteal phase?
Granulosa cells become large lutein cells –> progesterone
Some of theca interna become small lutein cells
What is the action of progesterone?
Acts at hypothalamus to depress LH and FSH secretion
- Direct negative feedback by acting on arcuate nucleus to reduce GnRH pulse frequency
- Inhibiting positive feedback effect of oestrogen
What is the pathway of oestrogen synthesis in the luteal phase?
Small luteal cells secrete androgens which pass to the large luteal cells to convert to oestrogen
What do you stain the zona pellucida for?
Glycoproteins
What is the coelomic epithelium?
The outer lining of the gonads
In development, the coelomic epithelium, + mesenchyme and gonadal stem cells makes up the indifferent gonad.
List the steps of oocyte-follicular unit development
Primordial follicle Preantral follicle Antral follicle Preovulatory follicle Ovulation Corpus luteum Corpus albicans
Define atresia
The degeneration of those ovarian follicles which do not ovulate during the menstrual cycle
From any of primordial follicle, preantral follicle, antral follicle
Describe the conversion from primordial to preantral follicle, including regulation and hormonal output
Major growth phase 10-120micrometers diameter
Lots of RNA and protein synthesis
No reactivation of meiosis from dictyate stage
ZP secreted by oocyte
Granulosa cells proliferate and develop several layers
Stromal cells condense to theca
Does not depend on exogenous hormones, doesn’t produce hormones
How do nutrients reach the oocyte in the primordial follicle?
Avasuclar
Dependent on granulosa cells transferring nutrients
Describe the conversion from preantral to antral follicle, including regulation and hormonal output
Little further oocyte growth but RNA continues to rise
Granulosa cells proliferate to many layers and commense follicular fluid secretion and formation of an antrum
Oocyte surrounded by cumulus oophorus
Granulosa cells develop FSHR and require FSH, thecal LHR req LH
Under LH stim thecal cells make androgens
Some pass to granulosa cells, which in presence of FSH convert androgens to oestrogens.
Inhibin production starts to rise as antrum develops - stimulate androgen output by thecal cells and its conversion to oestrogens
Positive feedback of oestrogens on granulosa cells that made them.
Vascularisation within theca layer
Where does the oestrogen biosynthesis pathway diverge from the testosterone one?
At testosterone! Then converted to oestrogens ie oestradiol 17beta instead of 5-alphaDHT
What is the other word for an antral follicle?
Graffian follicle
Describe the formation of the preovulatory follicle
Positive feedback effects of oestrogen lead to a rapid increase in oestrogen output
The thecal layer becomes hyperaemic and its output of androgens rises, further increasing oestrogen output.
Follicular fluid secretion increases rapidly
Follicular antrum swells
Req high levels LH.
Granulosa cells develop LH receptors and start synthesising progesterone under LH secretion.
Describe the preovulatory oocyte
In the preovulatory follicle, the high levels of LH reactivate oocyte meiosis (prophase nuclear membrane breaks down
When do the stages of oocyte meiosis take place?
Before birth until meiosis prophase I
Preovulatory follicle in ovarian cycle (ie high LH) –> reactivates
Primary oocyte through Meiosis I metaphase, anaphase, telophase
Secondary oocyte immediately into second meiotic division
Arrests a second time in second meiotic metaphase
Describe the first meotic division in oocytes
Unequal
Produces small first polar body and a large oocyte
Describe ovulation
LH + Prostaglandins from oocyte trigger follicle surface to thin and rupture at the stigma
Oocyte released to the surface of the ovary in its cumulus oophorus carried in follicular fluid
Antrum collapses and is invaded by blood vessels
Some granulosa cells transform to large lutein cells
Some thecal cells mingle with them as small luteal cells
Corpus luteum has formed
What is the corpus luteum otherwise known as?
Post-ovulatory follicle
Describe the corpus luteum
Large luteal cells produce progesterone
Small luteal cells continue to produce androgens
Androgens pass to the large luteal cells which then convert them to oestrogen
Inhibin is secreted in large amounts
LH necessary - after 14 days corpus luteum dies (luteolysis) unless high levels of luteotrophic LH-like activity is supplied in the pregnant state
Draw a diagram of the conc of different hormones during the ovarian cycle
x
Describe the formation of progesterone
Starts in pre-ovulatory follicle by granulosa cells under influence of LH(!)
Then continues after ovulation by luteal cells of corpus luteum
What selects the dominant follicle?
- Cytokines?
- FSH –> IGF-1 or IGF-2
IGF mediates LH stimulation of androgen output
FSH suppresses IGFBPs IGF binding proteins that normally neutralise IGF action
Possible that IGFBP produced by follicles with least good supply of FSH or fewer FSH receptors
AKA THE FOLLICLE WITH THE BEST FSH WILL GROW - Inhibin may also be involved in maintenance of a dominant follicle - stimulates androgen production
Draw a diagram of selection of the dominant follicle
x
What is the word used to describe mucus elasticity?
Spinnbarreit
How stretchy mucus is before it breaks
What does ferning represent?
The different carbohydrates being expressed on glycoproteins that make up mucus (along with mucin)
What is the change in basal body temperature with menstruation?
1 degree
What makes the pituitary?
Anterior = Rathke's pouch in roof of mouth Posterior = neurectoderm (hence why it has the neural connection with the hypothalamus)
List the cell types and functions of the anterior pituitary
Gonadotrophs: LH FSH Lactotrophs: prolactin Somatotrophs: GH Corticotrophs: ACTH Thyrotrophs: TSH
What do the different regions of the hypothalamus regulate?
Rostral = somatostatin and TRH
Intermediate = TRH, somatostatin, leptin, NPY, GnRH
Caudal: Sympathetic system regulation
How many forms of GnRH are there?
2 but one gene
Central 10 aa ending in Gly-Lys-Arg sufficient to stim ant pit
What is the evidence for the control how gonadal hormones are secreted in the male?
Male
1. Administration of testosterone - LH decreases and pulsatility decreases/castration - LH increases and pulsatility increases
What is the similarity that can be drawn between castrated males and post-menopausal women?
Lost oestrogen
Concs FSH and LH much higher (FSH becomes higher than LH, whereas before other way round)
Which form of oestrogen spikes?
Oestradiol (as oppose to oestrone)
What is the pelvic clock?
Phrase to describe the phenomena that follicular dynamics control the timing of the follicular phase
Summarise the evidence that gonadal hormones provide the main control of LH and FSH secretion
- Administration of testosterone to males
- Post-menopause
- Bolus administration oestradiol
- Ab against inhibin (only alters FSH conc)
What are the control points for LH and FSH secretion?
Frequency and/or amplitude of GnRH pulsing
Sensitivity of gonadotrophs to GnRH pulses
Summarise the sites of actions of the feedback effects of gonadal hormones
Oestrogen pit (controls LH) and hypo
Progesterone hypo
Inhibin pit only
Summarise the evidence for the mechanism of gonadal hormones acting
- Ovariectomied ewes GnRH levels vary with LH conc. Inject surge of oestrogen, LH falls then surges.
- Destroy GnRH-producing hypothalamic nuclei. Produce with invariant pulses of exogenous GnRH. If continuous, concs LH and FSH fall.
- Infuse oestrogen locally into arcuate nucleus, reduces GnRH pulse amplitude. Infuse progesterone locally, reduces GnRH pulse frequency.
What controls LH secretion?
Pituitary
Oestrogen induced alterations in sensitivity of gonadotrophs to hypothalamic GnRH
Pulsatility essential
What is the GnRH pulsatility called? Why is it needed
Circhoral release every 2h
Otherwise pituitary desensitisation
Summarise control of hormone release at the hypothalamus
Negative feedback:
Arcuate nucleus
Progesterone reduces GnRH pulse frequency
Oestrogen reduces GnRH pulse amplitude
Positive feedback
Oestrogen surge –> GnRH surge. Unsure where in ant hypo? This is blocked by progesterone in positive feedback suppression
How does the shape of LH pulsatility change?
Amplitude decreases (oest rising) till ovulation, then amplitude increases (oest effect blocked by progesterone and oest conc down) and freq decreases (progesterone effect)
How do LH levels change with puberty?
- Nocturnal augmentation of LH-secretion in early-mid puberty
- Establishment of high basal levels with no diurnal rhythm
What changes first in puberty out of FSH LH GnRH, hormonally? Proof?
GnRH pulsing - NB according to next lecture adrenarche first
Exogenous GnRH pulses initiate puberty
Brain tumours which activate premature GnRH production lead to premature puberty, and tumours that prevent GnRH production lead to delayed puberty.
Removal of GnRH pulses returns the pubertal individual to pre-puberty
What causes pubertal rise in GnRH? Why do we think so?
Candidates
1. Leptin:
- puberty begins consistently at 47kg for girls and 55kg for boys. Maybe triggers puberty, sensed by body fat stores.
- Also some human genetic disorders in leptin result in failure of puberty.
- Receptors for leptin present in the hypothalamus (some are in the arcuate nucleus)
- Overweight children tend to enter puberty earlier than lean peers.
2. Neurokinin B, Kisspeptin
- Genetic defect in families in Turkey in which more than one member didn’t go through puberty (severe congenital gonadotropin deficiency). Mutation in two genes: TAC and TACR3.
- TAC3 –> neurokinin B. TACR3 –> its receptor.
- Neurokinin B highly expressed in neurons that also express kisspeptin, a regulator of gonadotropin-releasing hormone secretion.
3. Day length: melatonin and other pineal secretions may inhibit reproductive function.
- Lesions of pineal gland lead to precocious puberty
- Secretory tumours of pineal gland leads to delayed puberty.
- Seasonality of females to reach menarche at a certain time of year
4. Sensory deprivation
-Blind and deaf children undergo early puberty
5. Stress
- Lab animals: certain stressors can delay sexual maturity.
- Opposite also proposed, stress during infancy and childhood can accelerate puberty.
Evidence: girls who grow up in the absence of a biological father, especially with a stepfather present, tend to enter puberty earlier.
6. Pollutants
- some chemicals used in industrial synthesis of plastics act as weak oestrogens (xenoestrogens). May accelerate puberty.
- Some pollutants like dioxins and polychlorinated biphenyls may delay male puberty.
7. Altitude
- For every 100m increase in altitude, puberty delayed by 3 months.
- Low pO2 might suppress metabolism?
8. Genetic factors (15% variation)
- Black girls 1 year earlier white girls
- identical mothers and daughters
-CYP3A4 variants (degrades testosterone so high activity form leads to high oestrogen:testosterone ratio)
What is the current trend of menarche?
Falling by approx. four years
Which environmental factors affect reproduction?
Light-circadian rhythms Circuannual rhythms Social stress and social interactions Diet Coitus (in some animals sex induces fertility increase)
Describe Soay sheep and what they tell us
Triggered by circannual rhythms?
Females copulate in short days so lambs born in Spring and can build up their strength.
Females copulate with up to 7 males in 2 day oestrus - 74% twin heteropaternity. Males copulate up to 13 times a day.
Describe Talapoin monkeys and what they tell us
Social stress/interactions affecting reproduction
With no female present, dom and sub males have equal testosterone
With female, dom > subordinate monkey testosterone
How can hormones affect your behaviour?
- Direct via action on brain i.e. testosterone
- Indirectly by non-neuronal action in you i.e. leptin
- Affects behaviour of others towards you by an action in you i.e. oestrogens
How does testosterone affect sexual behaviour in men?
Hypogonadal men age 40 following surgery for testicular tumour
Given testosterone will restore energy and libido
Will not enhance them in eugonadal men.
Without test freq of sexual thoughts decreases and energy decreases.
How do hormones affect behaviour of others towards you?
Most sexual activity occurs at time of peak fertility
Ovariectomy decreases male interest
Application of topical oestrogen to the vagina increases sexual attractiveness. Pheromones? Hard to control
