Puberty

• Transition from non-reproductive to reproductive state - mature gametes. • Profound physiological & psychological changes. • Secondary characteristics develop (primary are present at birth)

Adrenarche (pubarche) - Andrenal androgens: * Adrenarche originates from maturation of cells in the adrenal gland * Release of androgens leads to pubarche which is the appearance of pubic and axillary hair Gonadarche * Gonadarche follows adrenarche, and is HPG axis driven. * Synthesis and secretion of pituitary peptide hormones- LH and FSH, which activate gonadal function The two combined events lead to puberty, but are independently regulated LH stimulates gonadal steroid synthesis & secondary sex characteristics FSH stimulates growth of testis (male) and folliculogenesis with steroid synthesis (female)

Marked by a change in adrenal secretion as a result of remodelling the adrenal glands from childhood. The zona reticularis isn’t really apparent in the neonate (infant) and only starts to develop as an independent zone as adrenarche occurs. Secretion of… * Dehydroepiandrosterone (DHEA) & DHEAS (DHEA with sulphur to become more soluble in plasma) - made from zona reticularis . Responsible for axillary & pubic hair (pubarche). * Increasing gradually from around age 10, peaking in the mid 20s, then they decline throughout life. * Other adrenal steroids are not affected. Possible causes… * Unknown molecular trigger * Leptin or insulin possibly related to body mass * Normal remodelling of adrenal glands.

DHEAS enters the circulation and is transported to target tissues where it can be converted to testosterone or DHT.

• Appearance of pubic / axillary hair resulting from adrenal androgen secretion (adrenarche). • Associated with acne • Increased sebum production • Infection, abnormal keratinization Considered precocious before 8 years (girls) or 9 years (boys

Sebaceous PSU’s * These have a large sebaceous gland and secrete sebum under the influence of androgens. * Acne can develop as pores become blocked with sebum and/or infected. Vellous PSU’s These are fine hair that covers the body. Can differentiate into 2 different types of hair via androgen exposure? 1) Terminal PSU’s - Beard * Terminal PSU’s develop into moustache and beard hair 2) Apocrine PSU’s - Axillary and Pubic * Apocrine PSU’s located in armpits and groin go on to form pubic and axillary hair. Also scent glands in skin

• HPG axis is first activated at 16th gestational week and pulsatile GnRH secretion occurs in foetus until 1-2 years postnatally. • GnRH neurones ‘restrained’ during postnatal period of 10 years or more and reactivated at gonadarche when there is a gradual rise in pulsatile release of GnRH. • Increase in Kisspeptin promotes GnRH leading to gonadotrophins and ultimately gonadal steroidogenesis. • Reactivation of hypothalamic GnRH leads to activation of gonadal steroid production leading to production of viable gametes

• Pre-puberty: GnRH neurons are “restrained” during the postnatal period, lasting 10 years or more . While some pulsatile release occurs, it is less frequent and consistent compared to later stages • Early-mid puberty: There is a gradual rise in the pulsatile release of GnRH as the hypothalamic-pituitary-gonadal (HPG) axis reactivates. This pulsatile release becomes more consistent, particularly during the day • Mid-late puberty: As puberty progresses further, the pulsatile release of GnRH becomes more consistent • Adult: In adults, a consistent pulsatile release of GnRH occurs throughout the day. LH often serves as a surrogate measure for GnRH activity, which is difficult to measure directly .

• Epiphyses are the rounded ends of bones that initially form separately to long bones and gradually fuse to the main shaft of the bone as an individual ages. • The initially low levels of estrogen seen as the HPG axis reawakens promotes linear bone growth and is responsible for initial rapid growth spurt • As estrogen levels become higher you get epiphyseal fusion and growth stops

Complex interaction between… * Growth hormone * Estrogen (boys and girls) * Approximately 2 years earlier in girls. Biphasic effect of estrogen on epiphyseal growth • Low levels of estrogen as HPG axis reawakens promotes linear growth & bone leading to initial rapid growth spurt. • High levels of estrogen promote epiphyseal fusion (at the ends of the bone) & growth stops. Girls have a earlier and shorter growth spurt whereas boys have a later and longer growth spurt

Clear that it is maturational event within the CNS but details not yet elucidated. Inherent (genetic) * Maturation of 1000-3000 GnRH synthesising neurones. * May be environmental/genetic factors. Body fat/nutrition * During the last century puberty has occurred earlier as nutrition has improved. * Anorexia nervosa or malnutrition delays puberty * Theory that 17-18% body fat required to initiate puberty and 22% to maintain menstrual cycle – possible link with Leptin levels. Kisspeptin * Some mutations in Kisspeptin activate or inactivate puberty initiation

Consonance refers to a smooth ordered progression of changes. Regardless how long each pubertal transition takes in any given individual, the order in which the changes happen remains the same

Tanner scale

Stage 1: pre-pubertal * No sexual hair * Flat-appearing chest with raised nipple Stage 2: 8-11.5 * Pubic hair appears (Pubarche) * Testicular enlargement * Breast bud forms (thelarche) Stage 3: 11.5-13 * Coarsening of pubic hair * Increase in penis size/length * Breasts enlarge, mound forms Stage 4: 13-15 * Coarse hair across pubis, sparing thigh * Increase in penis width/glans * Breast enlarges, raised areola, mound on mound Stage 5: >15 * Coarse hair across pubis and medial thigh * Penis and testis enlarge to adult size * Adult breast contour, areola flattens

• Increasing need for independence • Increasing sexual awareness/interest • Development of sexual personality

Gonadotrophin-dependent (central) precocious puberty Consonance maintained * Excess GnRH secretion - idiopathic or secondary * Excess gonadotrophin secretion - pituitary tumour Gonadotropin-dependent precocious puberty is associated with accelerated linear growth for age, advanced bone ages and increased levels of FSH, LH, estradiol and testosterone. Central precocious puberty Treatment… * Case-by-case assessment depending on age, psychological benefits, patients/carers wishes and expectation. * GnRH analogues to suppress puberty until 11-12 years of age if appropriate. * Surgery, radio or chemotherapy.

Gonadotrophin-independent (peripheral) precocious puberty - Loss of consonance * Testotoxicosis - activating mutation of LH receptor leading to early androgen production by Leydig or Theca cells. No FSH increase (eg no spermatogenesis). * Sex steroid secreting tumour or exogenous steroids – secondary sexual characteristics * McCune Albright - constitutive activation of adenylyl cyclase - hyperactivity of signalling pathways including those of gonadotrophin hormones. * Congenital adrenal hyperplasia – androgen production by the adrenal glands. Gonadotropin-independent precocious puberty is associated with suppressed FSH or LH levels and increased estrogen or testosterone.