Puberty Physiology Notes

Puberty

  • Puberty is the time when the gametogenic and endocrine functions of the gonads develop to the point where reproduction is possible (Gonadarche).
  • Gonads: ovaries and testes.
  • Dual function:
    • Production of germ cells (ova, spermatozoa).
    • Secretion of sex hormones (estrogens, androgens).
  • Both functions depend on gonadotropin secretion from the anterior pituitary.

Hypothalamic-Pituitary-Gonadal Axis

  • Fetus and Infancy (Both Sexes):

    • GnRH is present in the hypothalamus at 14-16 weeks gestation.
    • Gonadotrophs are present in the anterior pituitary from 10 weeks.
    • The hypothalamic-pituitary system is functional by approximately 23 weeks gestation.
    • A surge in LH and FSH occurs in utero, followed by a second peak in the postnatal period.
    • These peaks cause corresponding peaks in sex hormones.
    • The neonatal peak may be due to withdrawal from the high steroid environment of the womb.

  • Childhood:

    • GnRH release is prevented through unknown mechanisms.
    • Plasma gonadotropin levels are low, especially between 6-8 years old.
    • Gonads are quiescent, and levels of sex steroids are low.
    • Removal of gonads during childhood does not cause a massive elevation of LH/FSH.
    • Pulsatile injections of GnRH in immature monkeys can induce normal menstrual cycles.

  • Prepuberty Regulatory Mechanisms:

    • GABA neurons inhibit GnRH neurons.
    • NPY and endorphins also play inhibitory roles.
    • Glutamate neurons stimulate GnRH neurons.
    • Melatonin inhibits LH and FSH release.
    • Testosterone (T) and Estradiol (E2) provide negative feedback.

Pubertal Development

  • Between 7-10 years, there is a slow increase in estrogen and androgen levels, followed by a more rapid rise in the early teens.
  • Pubertal development is divided into 5 stages (Tanner Stages) for:
    • Breast development (girls).
    • Pubic hair development (both sexes).
    • Genital development (boys).

Tanner Stages

  • These stages are used to clinically assess the progression through puberty, evaluating the physical development of breasts, pubic hair, and genitals.

Order of Events in Girls

  • Thelarche: breast development.
  • Pubarche: development of axillary and pubic hair.
  • Menarche: first menstrual period. Initial periods are typically anovulatory, with regular ovulation appearing about a year later.
  • Estrogen effects:
    • Thickening of vaginal mucosa.
    • Enlargement of uterus and cervix.
    • Increased number and length of uterine glands.
    • Proliferation of stroma and endometrium.
    • Production of cervical mucous.
  • Breasts: Progesterone (for alveoli), estrogen (for ducts), along with other hormones contribute to development.

Order of Events in Boys

  • Testes enlarge to greater than 2.5 cm length (3 ml volume).
  • Androgenic effects of testosterone:
    • Lengthening of the penis.
    • Enlargement of the scrotum, prostate, and seminal vesicles.
    • Development of pubic and axillary hair.
  • Spermarche: first appearance of spermatozoa in the early morning urine (mean age 13.4 years), typically occurring around genital stage 3-4 and pubic hair stage 2-4.

Male Puberty – Additional Changes

  • External genitalia development.
  • Internal genitalia: Seminal vesicles enlarge and secrete fructose; prostate and bulbourethral glands enlarge and secrete.
  • Voice: Larynx enlarges, vocal cords increase in length and thickness, causing the voice to deepen.
  • Body conformation: Shoulders broaden, muscles enlarge.
  • Hair: Facial hair growth, temporal hair recession, male pattern pubic hair (triangle with apex up), hair on chest, axillae, around anus, with a general increase in body hair.
  • Skin: Sebaceous gland secretion thickens and increases, predisposing to acne.

Adrenarche

  • Onset of increased secretion of adrenal androgens, occurring around 8-10 years in girls and 10-12 years in boys.
  • Due to increased activity of CYP17 (P450c17; 17α-hydroxylase, 17,20-lyase), leading to:
    1. Increased conversion of pregnenolone to 17α-hydroxypregnenolone.
    2. Increased conversion of progesterone to 17α-hydroxyprogesterone, resulting in more androgen formation.
  • Decreased activity of 3β-hydroxysteroid dehydrogenase, leading mainly to the production of dehydroepiandrosterone (DHEA).

Growth Spurt

  • Occurs in both sexes due to growth hormone, estrogens, and androgens.
  • Growth cessation is due to the closure of epiphyseal plates of long bones by estrogen.

Body Composition

  • Before puberty, boys and girls have similar lean body mass, skeletal mass, and body fat.
  • After puberty:
    • Men have approximately 1.5 times the lean and skeletal body mass compared to women.
    • Women have approximately 2 times the body fat compared to men.
  • Men have twice the number of muscle cells and 1.5 times the muscle mass of women.
  • Men have a higher hematocrit.

Control of Onset of Puberty

  • Variable age: typically between 9-14 years for males and 8-13 years for girls.
  • In Europe and the USA, the age of puberty has been declining at a rate of 1-3 months per decade over the last 175 years.
  • Onset begins with pulsatile gonadotropin secretion during sleep, driven by pulsatile GnRH release.
  • Kisspeptin-GPR54 signaling plays a crucial role in the initiation of puberty.

Feedback Sensitivity

  • The relative sensitivity of gonadotropin release to negative feedback by sex steroids changes with age:
    • High sensitivity in the fetus, infancy, and childhood.
    • Low sensitivity during puberty and adulthood.

Factors Influencing Timing

  • Genetic factors.
  • Nutrition: Critical body weight is necessary for puberty to occur (e.g., athletes and girls with anorexia nervosa may experience amenorrhea).
  • Leptin levels: There may be a link between weight and puberty due to leptin, which is secreted by fat cells and produces satiety (based on mice studies).
  • Geographical location and exposure to light.
  • Prenatal exposure to the rainy season and altitude of residence can also influence the timing of sexual maturation.

Precocious Puberty

  • True early puberty (Gonadotropin-dependent).
    • Central precocious puberty: First signs of puberty occur before 8 years in girls or 9 years in boys.
    • Constitutional early puberty: Signs appear more than 2 standard deviations earlier than the mean but not before 8 years for girls or 9 years for boys.
    • More common in girls.

Causes of Precocious Puberty

  • Hypothalamic diseases: Hamartomas, tumors, cysts, infections, hydrocephalus.
    • Increased GnRH release or interruption of pathways that normally inhibit GnRH.
    • Lesions in experimental animals.
  • Ectopic secretion of GnRH.

Potential Treatment

  • GnRH analogs to suppress elevated LH and FSH.

Precocious Pseudopuberty

  • Peripheral precocious puberty; Gonadotropin-independent.
  • Early development of secondary sexual characteristics without gametogenesis.
  • Elevated androgens/estrogen, suppressed LH & FSH.
  • Occurs due to abnormal early exposure to androgens in males or estrogens in females.

Causes of Precocious Pseudopuberty

  • Congenital adrenal hyperplasia.
  • Adrenal tumors.
  • Gonadal tumors.
  • Familial gonadotropin-independent (Familial male-limited precocious puberty): Increased sensitivity of LH receptors due to activating mutation in the G-protein, coupling the receptors to adenyl cyclase, leading to early Leydig cell maturation and increased testosterone.

Delayed or Absent Puberty

  • Pathological delay:
    • Lack of thelarche by age 13 or menarche by age 16 in girls.
    • Testicular development not commenced by age 14 (or volume < 4 ml) in boys.
  • Hypothalamic causes:
    • Kallmann syndrome: Hypogonadotropic hypogonadism + hyposmia/anosmia due to disordered migration of GnRH cells during development.
    • Disturbances of GnRH secretion.
    • Mutations of GnRH receptor gene.
    • Mutations of leptin gene or leptin receptor gene.
    • Mutations of GPR54.
    • Mutations of Kiss1 gene.
  • Pituitary causes:
    • Panhypopituitarism (pituitary insufficiency).
    • Tumors of pituitary.
    • Radiotherapy of the hypothalamic-pituitary region.
    • Mutations of the β-LH or β-FSH gene.
    • Mutations of the LH or FSH receptor gene.
  • Gonadal causes:
    • Gonadal dysgenesis, including Turner syndrome.
    • Ovarian failure due to trauma, torsion, post-infection, or post-radiation.
  • What if puberty commences, but there is primary amenorrhea?
    • Distal obstruction
    • Imperforate hymen
    • Transvaginal septum
    • Lack of Mullerian structures (undeveloped or absent uterus)
    • Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome
    • Type 1
    • Type 2
    • Complete androgen insensitivity syndrome