Puberty and menopause

How puberty starts

• The GnRH pulse generator, active in fetal life and in the first months after birth (mini-puberty), is restrained through childhood. Puberty is the reawakening of pulsatile GnRH, driven by kisspeptin.
• Leptin is permissive: girls who are very thin start puberty only after gaining fat. Better nutrition explains the secular trend to earlier menarche over the last century.
• The first hormonal sign is sleep-entrained nocturnal LH pulses.
• Adrenarche (adrenal DHEA sulphate rising from about 6–8 years) is separate from gonadal puberty and gives pubic and axillary hair; a girl with absent ovaries still grows sparse sexual hair.
• In complete androgen insensitivity (46,XY), breasts develop because testosterone is aromatised to oestradiol, but sexual hair is absent.

Sequence in girls and boys

• Tanner breast stages: 1 prepubertal; 2 bud with areolar enlargement; 3 breast and areola enlarge together; 4 areola forms a secondary mound; 5 adult contour.
• The growth spurt comes from sex steroids amplifying GH pulses, so IGF-1 reaches its lifetime peak; oestrogen closes the epiphyses in both sexes (a man unable to aromatise androgens keeps growing).
• The uterus changes from tubular (cervix larger than corpus) to pear-shaped (corpus twice the cervix) with a visible endometrial echo. The pituitary also enlarges normally at puberty.
• Early cycles are anovulatory because positive feedback is immature: irregular, sometimes heavy periods. Dysmenorrhoea appears once ovulation begins.
• Pubertal gynaecomastia in boys reflects a transient oestrogen–androgen imbalance and usually regresses.

Precocious puberty

• Defined as signs before 8 years in girls and 9 years in boys.

• Central precocity is treated with a GnRH agonist because early sex steroids close the epiphyses: the child is tall now but becomes a short adult (bone age well ahead).
• An hCG-secreting tumour causes puberty in a boy (hCG acts on Leydig LH receptors) but not in a girl, because ovarian oestrogen needs FSH as well (two-cell model).
• Premature thelarche: isolated breast development at 6 months to 2 years with normal growth and bone age; benign.
• A newborn girl has a relatively large uterus and endometrial stripe from maternal oestrogen.

Delayed puberty

• Girls: no breast development by 13 years; boys: no testicular enlargement by 14 years.
• Constitutional delay: commonest; delayed bone age, family history of late menarche, prepubertal LH and FSH, normal smell and karyotype.
• Hypogonadotrophic: Kallmann syndrome (anosmia), low weight, chronic illness, pituitary disease.
• Hypergonadotrophic: gonadal failure, especially Turner syndrome (45,X).

Menopause

• Oocyte pool: about 6–7 million in fetal life, 1–2 million at birth, 300,000–400,000 at menarche; menopause comes when it is exhausted (average about 51 years).
• Diagnosis: 12 months of amenorrhoea in a woman over 45 not on hormones.
• Perimenopause: fewer follicles make less inhibin B, so FSH rises; follicles are recruited faster, so the follicular phase and cycle shorten (23–24 days) before cycles become irregular and anovulatory. Unopposed oestrogen can then cause heavy, irregular bleeding. An undetectable AMH predicts menopause within a few years.

• Obese postmenopausal women make more oestrone in fat, so they have more endometrial hyperplasia and cancer.
• Hot flushes: oestrogen withdrawal narrows the hypothalamic thermoneutral zone, so a tiny rise in core temperature triggers heat-loss responses. Surgical menopause is abrupt, so symptoms are more severe.
• Genitourinary syndrome: thin vaginal epithelium, dryness, dyspareunia, urgency; low-dose vaginal oestrogen treats it without systemic effect.
• Bone: accelerated trabecular loss. Lipids: LDL rises, HDL falls; cardiovascular risk increases.
• Transdermal oestrogen avoids hepatic first pass and carries the lowest risk of venous thromboembolism.

Premature ovarian insufficiency

• Before 40 years: amenorrhoea, low oestradiol and FSH raised on two samples 4–6 weeks apart.
• Causes: Turner syndrome, fragile X premutation, autoimmune (associated with Addison disease and steroid-cell antibodies), chemotherapy (alkylating agents such as cyclophosphamide are most gonadotoxic), radiotherapy, surgery. Smoking brings menopause earlier by accelerating follicle loss.

Remember Girls: breasts first, growth spurt early, menarche last; boys: testes first, growth spurt late.

Exam trap Central precocious puberty has raised gonadotrophins that rise with GnRH; peripheral has suppressed gonadotrophins.

Exam trap The postmenopausal oestrogen is oestrone from fat, not oestradiol from the ovary.