1. A little girl runs out to the yard where her father is working, and asks him, "Daddy, what's sex?" Her startled father sits her down, and tells her all about the birds and the bees. He tells her about conception, sexual intercourse, sperm and eggs. He goes on to tell her about puberty, menstruation… the works… By the time he's finished, his daughter is somewhat awestruck with this sudden influx of bizarre new knowledge. Her father finally asks: "So what did you want to know about sex for?" "Oh, mummy said to tell you lunch would be ready in a couple of secs..."

2. BIOL30001 Reproductive Physiology Puberty Geoff Shaw Zoology Reading:EssRep7 Ch 3; Johnson & Everitt (2000) Chapter 7. Grumbach & Styne (1998) in William’s Textbook of Endocrinology. Ed Wilson JD et al. pp 1509-1625. Knobil & Neill (Eds) Vol 2. Chapters 40, 41 & 42. Dungan et al (2006) Kisspeptin neurons as central processors in the regulation of gonadotrophin-releasing hormone secretion. Endocrinology 147: 1154-8 Colledge WH (2008) Kisspeptins and GnRH neuronal signalling. Trends in endocr. Metab. 20: 115-121

3. Puberty period of transition from adolescence to adulthood. In humans takes 4-5 years development of secondary sexual characters many other physical and endocrine changes menarche – first menstruation first ejaculation

4. Boy age 5 yrs 3 mo height =9.5 years bone-age 13.5 yrs muscular build pubic hair penis large acne deep voice right testis swollen Seminiferous cords outside the tumour no maturation to spermatids or spermatozoa Right Testis interstitial cell tumour

5. adolescent growth spurt –minimum growth velocity –peak height velocity –decrease and cessation of growth and start of epiphyseal fusion growth spurt in boys later than girls sex differences in pattern of growth –shoulders –hips Growth Hormone and sex- steroids increasing bone density Changes in growth 24681012141618 8 12 16 20 22 24 rate of growth (cm/year) GirlsBoys Age (years)

6. Female development during puberty: From J&E figs 7.2,7.3,7.6a after Tanner 8 9 10 11 12 13 14 15 age (years)

7. Secondary sexual characters develop during puberty: male From J&E figs 7.4,7.6b after Tanner

8. Individual variation in timing of puberty boys all aged 14 yrs girls – average and ranges

11. Adrenal changes: Adrenarche Adrenal changes –from 8 years old until about 13-15 years –increased secretion of dehydroepiandrosterone DHEA and DHEAS (DHEA-sulphate) –weak androgens but very high concentrations –independent of glucocorticoid and mineralocorticoid –promotion of pubic and axillary hair growth –not closely linked to puberty

12. Thelarche Pubertal changes due to oestrogens –breast development –hip fat distribution –increase in vaginal cell: glycogen content secretions –uterine development

13. Gonadotrophins and gonadal steroids - female Increasing gonadotrophins increasing oestradiol some androgens (DHEA) from adrenal Based on J&E fig 7.7a 12345 710.511.61314 bone age Tanner pubertal stage hormone level FSH LH plasma oestradiol

14. Gonadotrophins and gonadal steroids-male increasing gonadotrophins increasing androgens small amounts of oestrogen from testis; more from peripheral aromatization of testosterone based on J&E fig 7.7b 1234adult 7.71213.715.7adult bone age Tanner pubertal stage hormone level FSH LH plasma testosterone

15. Levels of control for puberty Organization Hypothalamus Portal vessels Pituitary Gonads Characteristics GnRH oscillator (pulse generator) Frequency of pulses hormonal signal: pusatile frequency and amplitude modulated signal – pulsatile secretion Activation of gonadal gondadotrophin receptors amplitude modulated act via gonadal steroid receptor MBH GnRH neurons GnRH gonadotropes LH & FSH testes ovaries TESTOSTERONE OESTRADIOL

16. Gonadostat Hypothesis From J&E fig 7.9 reflects changing characteristics in the HPG feedback system, but may be consequence rather than cause of puberty. note: (+)-ve feedback system develops late in puberty in females. first cycles often anovulatory

17. Maturation of CNS 0 10 20 30 40 0 100 200 300 400 020406080100120140 FSH (ng/ml) LH (ng/ml) Age (weeks) bilateral castration Rhesus macaque after castration, FSH and LH rise to adult levels until week 20, then fall to basal until after week 120 result from changed GnRH output in absence of any changes in gonadal steroid levels similar effects seen in agonadal humans - eg in Turner’s or Keinefelter’s syndrome restraint

18. Induction of gonadotrophin pulses in immature rhesus monkey by hourly GnRH pulses over 110 days Note the first induced oestradiol peak does not induce a full LH surge After cessation of GnRH pulses ovarian cycles cease and subsequent implantation of an oestradiol pellet does not induce an LH surge in the absence of GnRH pulses Maturation of CNS From J&E fig 7.11

19. Kisspeptin found to regulate HPG axis in 2003 various peptides derived from a 145 a.a. protein encoded by Kiss 1 gene found in hypothalamus act via G-protein coupled receptor GPR54 GPR54 found on GnRH neurons exogenous kisspeptin stimulates GnRH secretion mice with disrupted Kiss 1 or GPR54 prevents puberty onset of Kiss 1 expression in hypothalamus and increased GPR54 in GnRH neurons just before puberty administration of kisspeptin to prepubertal rats advances onset of puberty

20. Does kisspeptin drive puberty? gonads sex steroids E / T KISS Neuron + GnRH Neuron GnRH pituitary arcuate nucleus AVPV KISS Neuron - + + + + LH / FSH

21. A central role for kisspeptin? see: Dungan et al (2006) Kisspeptin neurons as central processors in the regulation of gonadotrophin-releasing hormone secretion. Endocrinology 147: 1154-8 adrenal SCN GnRH Neuron KISS Neuron body fat gonads GnRH glucocorticoids Other factors Vasopressin leptin sex steroids REPRODUCTIVE FUNCTION Environmental cues and endogenous rhythms ? ? ? + + -

22. Ojeda et al (2006) The neuroendocrine regulation of puberty: is the time right for a systems biology apporach? Endocrinology 147: 1166-74

23. Trend to earlier puberty changes not seen in most underdeveloped countries trend slowed/stopped in last 40 years photoperiod and other environmental cues nutrition –anorexia body weight potential role of leptin? From J&E fig 7.12

24. body weight and puberty From J&E fig 7.13 constancy in weights at onset of puberty and also growth spurt critical weight of about 47 kg for menarche for girls; boys mature about 55 kg malnutrition can delay puberty; moderately obese girls tend to have early menarche much individual variation

25. precocious puberty Lina Medina aged 5 years and 6 mo. youngest mother on record height age 6 y 6 m sexual development and menstruation began at 3 years onset of pregnancy at 4 years 10 months delivered healthy boy 2.9 kg by caesarean section at 5 years 7 months (from Escomel: Prese méd 47:744,875, 1939)

26. Summary: Puberty Transition – dramatic changes in sexually dimorphic structures, behaviour, activation of reproductive function Tanner stages activation of the HPG axis physiological changes  androgens and oestrogens Timing  activation and disinhibition of GnRH pulsatility developmental and environmental cues (eg nutrition/body wt)