RB3 L21 Notes PDF

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Lecture 21 Reproductive Biology 3 Notes...

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RB3 L21 – Puberty and Menopause Learning outcomes: 

To explain the mechanisms causing onset of puberty and reproductive maturity

(Keyword: HYPOTHALAMIC MATURATION) 

To describe the underlying basis for the menopause

(Keyword: OVARY DRIVEN)

Steroids and peptides  produced to provide negative feedback

Kisspeptin  drives GnRH action in the hypothalamus by acing directly on it

= 1st period More difficult to time puberty in males

Adrenarche:   

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The adrenal gland is a t the top of the kidney on both sides Adrenal cortex activated ~ 8yo Increased secretion of steroids from zona reticularis (DHEA, androstenedione, testosterone)  androstenedione is weaker than testosterone but it is its precursor  converts to testosterone ?role of increased production steroids? – to produce secondary sexual hair like pubic/axillary hair **NOT associated with timing of puberty, it’s just a marker for the termination of rapid brin growth  Adrenaline is secreted from the medulla

 The key event is HPG axis activation BUT GnRH secretion cannot be measured directly (Gonadotrophin secretion cannot be measured directly)  we are measuring LH & FSH as the outcomes that reflect GnRH secretion  GnRH secretion is pulsatile  every pulse of GnRH that goes to the portal blood causes a pulse of LH as a response  FSH is less important/ weaker response  There is progressive activation of hormones

 Mini-puberty of neonate  during the first 2-3 months of life the gonads are extremely active  in boys there is almost as much testosterone in the blood when they are born as much as there is when they are adults  there is overall gonadal activation  After that period the system switches off and during pre-puberty there are very low levels of LH  GnRH is released from the hypothalamus, passes via the portal system to the pituitary and there acts on GnRH receptors to release the gonadotrophins (LH, FSH) that then act on the gonads  During puberty the system gets activated again and there is pulsatile secretion that is characteristic of adult function  Any pathological, experimental or genetic bnormality in GnRH synthesis, storage, release or action results in partial or comlete failure of puberty and of gonadal funcion  Continuously infused GnRH does not restore its function if it is lost pullsatility is v important  a first GnRH pulse triggers an initial release of stored LH/FSH in a single pulse  at the same time more secretory granules containing LH/FSH move to plasmalemma  as a result of this self-priming granule mobilization, a 2nd exposure to GnRH results in a much larger primed release of LH  most important event in the initiation of puberty is activation of the hypothalamic

mechanism, which delivers GnRH pulses to the anterior pituitary

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Gonadotrophin secretion predominantly happens at night at the beginning of puberty  as puberty progresses and mainly in adult life, testosterone levels balance/ become more even across the 24hnot clear why this is happening Found by measuring testosterone levels in boys in the morning  Higher in the morning than later during the day Can predict the timing of puberty by picking up the nocturnal rise in LH

Gonadal Activity: 

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Testosterone - males o Birth: high in boys, then declines  “mini puberty of neonate” o Early puberty: secretion increases at night in boys o Mid-late puberty: increased during day as well Estradiol -females o Birth: very high, then declines  “mini puberty of neonate”, oestrogen production by the ovaries as well o Puberty: secretion increases AMH -females o Neonate: high and rises steadily through childhood o Puberty: “wobble”  steady rise of AMH, does not switch off completely indicating that there is some gonadal activity going on even if it is not gonadotrophin dependent o Can be measured at any age

Hypothalamic maturation theory  aims to explain how the maturation of hypothalamus regulates the patterns of hormonal release observed before and after puberty Castrated female monkeys:  

NO negative feedback Lack of gonadotrophin secretion  No LH & FSH

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Change in sensitivity  As the body produces more GnRH the organism becomes more sensitive to it Small pulses of GnRH after its infusion  become more regular after a while  hypothalamic GnRH secretion drives pubertal development  LH surges etc.

Puberty is not an “all or nothing response”  takes time to mature and establish its normal adult life function After menarche many girls DO NOT have regular cycles  take yars to establish  many cycles may be annovulatory Cycles become irregulr and annovulatory again as females are approaching menopoause Some syndromes are characterised by irregular cycles  cycle should be rehgular by late teens if not there is an issue

Kisspeptin drives GnRH secretion but what are the signals driving kisspeptin’s action? Probs body weight is a factor  specific body weight must be reached before entering puberty Exogenous kisspeptin was given to see if it will drive LH pulsatility which indicates that it drove GnRH pulsatility first Graph shows how LH pulses increased after kisspeptin was administered in a male In females it is thought that kisspeptin is what drives the ovulatory surge

Kisspeptin & GPR54 and Puberty: 

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Kiss-1 gene and its product, kisspeptin, discovered by scientists in Hershey, Pennsylvania, famous for its chocolate "Kisses (Hershey's Kisses)". Transgenic mice with deleted GPR54 (kisspeptin receptor) fail to progress through puberty Peripheral administration of kisspeptin to prepubertal rats stimulates LH secretion and induces

ovulation 

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Increase in KiSS-1 mRNA and/or GPR54 mRNA expression (RTPCR) during puberty The electrophysiological response of GnRH neurons to kisspeptin increases at puberty

Leptin:      

Secreted by fat cells and acts on the hypothalamus Regulates appetite and energy expenditure Metabolic signal – control of HPG axis with an impact on reproduction Mice: homozygous mutants (-/-) are infertile; reversed by leptin treatment Humans: leptin receptor signalling failure = obese and infertile (no GnRH secretion) = not as clear effects as in mice Leptin provides a key link between fat/weight and reproduction

Kisspeptin and Leptin:    

Kisspeptin neurones are sensitive to leptin  part of the mechanism underlying the idea that weight impacts on reproduction through the signalling of leptin on kisspeptin Kisspeptin neurones act as central processors of information determining how they will act on the reproductive system Relay signals from periphery to GnRH neurones Fasting decreases kiss1 mRNA? lack of leptin?

Puberty Timing:  

Boys (as a group) are different to girls  but any one individual boy or girl may be very different to the next Ex. 14 yo boys can be v different to each other  there is a range of normality  Are we getting taller? Is puberty happening earlier?  yes compared to 100 years ago because now there is better nutrition reach the desired bodyweight for entering puberty earlier  we are more reproductively fitted, reproduction is a activated earlier  Nutrition is key for entering puberty and appropriate/healthy development  malnutrition impairs development ex. WW2 kids  If one undergoes puberty very young  growth is impaired  the person ends up being v short

Kallmann’s Syndrome  Isolated GnRH deficiency

Boy is 17 yo (right) after receiving pulsatile GnRH he managed to develop He is 17 but looks like 14 yo (left)  underdeveloped due to lack of GnRH Super long arms  he has GH so his bones are growing but his limbs/long bones grow faster than his spine/short bones because his gonadal activity is low because gonadal activity does not affect the spine that much Why are older brothers often overtaken in height by their younger sisters during adolescence? Sex steroids act on the bones to stop their growth by acting on the epiphysis of the bones to fuse the growth plates so they do not grow more  females enter puberty earlier than males  females are taller than males in young ages Puberty is more easily timed and measured in girls due to the beginning of the menstrual cycles Are girls starting their periods earlier? not really, depends on the country Puberty is all about the hypothalamus driving gonadal development Summary – Puberty:    

ADRENARCHE: first sign but doesn’t regulate onset of puberty, it is just the maturation of the adrenal cortex HPG MATURATION: GnRH/LH activation at nightPUBERTY MENARCHE: only in females, can be recorded and know the beginning of puberty CRITICAL BODY WEIGHT: transgenic mice or people with no leptin – lack of puberty

Menopause:      

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Exhaustion of ovarian reserve Decreased oestrogen levels  irregular and non-

ovulatory cycles Symptoms of oestrogen deficiency  Hot flushes, loss of bone density Permanent cessation of menses following loss of ovarian activity Usually defined as >12 months of amenorrhoea Not only oocyte number depletes but also the follicles contained inside them deplete and they are not enough to get ovulatory and go through the process of follicular selection and maturation  huge variation between individuals The trajectory of each female’s follicular depletion is not yet well undersold  we do not know if there is a steady decrease, if it is fluctuating etc. we just know that by age 40 the majority of oocytes and follicles will have massively been depleted we need better markers for follicular activity

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It is not just the number of oocytes and follicles that is declining it is their quality as well Egg quality is declining with increasing age  young eggs are usually donated to older women

AMH:  good indicator of ovulation  Indirectly reflects the ovarian reserve because it is produced by pre-antral follicles and so it is indirectly reflecting the number of primordial follicles  Huge range of number of follicles between women  Serum AMH levels are highly correlated with AFC= antral follicle count  AMH is menstrual cycle independent and easily measurable  Predicts year of menopause  BUT histology needs to be observed along with AMH levels to predict menopause

 0 = last period  Estradiol levels fluctuate and then decline, they will keep declining after the last period  FSH levels increase  lack of negative feedback, high FSH is the biochemical way of diagnosing menopause because it is the only period when FSH goes really high  AMH levels will be undetectable after menopause Clinical Aspects of Menopause: Symptoms:  Menstrual cycle changes (irregular)  Hot flushes due to lack of oestrogen  Night sweats… Consequences:  Amenorrhoea  Osteoporos is  Cardio/cere brovascular disease Treatment:

 Hormone Replacement Therapy Summary – Menopause:    

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OVARY-DRIVEN problem: (AMH = marker) LACK OF ESTROGEN: undesirable symptoms, lack of oestrogen due to the lack of follicles HORMONE REPLACEMENT can reduce some symptoms Average age of menopause stayed approx. the same over last 150 years – depends upon number of follicles, does not have a big metabolic impact like puberty that can change due to malnutrition No menopause in men

Take Home Messages: PUBERTY:  driven by hypothalamic maturation  depends upon body weight/leptin  = reproductive maturity MENOPAUSE:  driven by lack of ovarian follicles  symptoms depend on sex steroids (possible weaker effects in men)  = reproductive decline...