delayed puberty

Question 1

Describe the pathophysiology of puberty

Answer 1

• Estrogen, “GnRH pulse generator”, is suppressed during childhood
• Puberty Starts with pulsatile noctural GnRH release.
• Stimulates the secretion of pituitary hormones: follicle-stimulating hormone (FSH) and luteinising hormone (LH)
  
  • FSH stimulates follicular cells,
  • LH -> oestrogen
    1. Thelarche,
       1. the breast bud appears at an average age of 9 years (range, 8–13 years)
       2. breast development is stimulated by oestrogen
    2. adrenarche,
       1. At the time of birth, the androgen-producing fetal zone of the adrenal cortex undergoes involution and remains quiescent until approximately 6 years of age, when adrenarche begins
       2. Adrenarche is defined essentially as the “pubertal transition of the adrenal gland” and is characterized by an increase in serum levels of dehydroepiandrosterone sulfate (DHEA-S), which is a direct response to adrenocorticotropin hormone (ACTH) stimulation.
       3. Androgen production - > hair growth
    3. pubarche,
       1. Androgen production - > hair growth
    4. peak height velocity (PHV),
       1. Oestrogen stimulates growth hormone (GH) secretion (pulsatile secretion) -> growth spurt ( growth potential of 25 cm)
    5. ultimately menarche occur average age 12.8

Question 2

describe pubertal physical changes in external genitalia

Answer 2

• Vagina:
  
  • increases in length
  • vaginal epithelium increase in superficial cells compared with parabasal and intermediate cell forms, which represents an estrogen-stimulatory effect.
  • Vaginal pH becomes more acidic approximately 1 year before menarche, representing the presence of lactobacilli.
  • Physiologic leukorrhea is frequently a hallmark indicative of the impending onset of menarche.
• Mons pubis
  
  • increases in size with the development of fat deposition
• Labia majora:
  
  • enlargement of the labia majora.
  • A particularly wrinkled appearance of the labia becomes more obvious,
• the clitoris increases slightly in size, and the urethral hillock becomes more prominent

Question 3

describe pubertal changes in uterus and ovaries

Answer 3

• Uterus:
  
  • Initially, there is a 50:50 size ratio between the uterine fundus and the cervix.
  • the cervix becomes one third the size of the entire uterus.
  • During childhood, the uterus usually lies in the midplane position.
  • Later stages in pubertal development primarily involve the myometrium, which is a reflection of response to ovarian hormonal stimulation.
  • The endometrium further develops after onset of secondary sex characteristics with resultant menstruation
• Ovaries
  
  • There seems to be a continuous growth of the ovaries throughout childhood

Question 4

describe the HP axis development

Answer 4

• inUtero GnRH is present, stimulating the release of gonadotropins by 10–18 weeks’ gestation
• In the fetus and term neonate, serum estrogen levels are noted to be approximately 5000 pg/mL at term, but this also reflects the conversion of fetal and maternal C-19 steroid precursors to estrogens by the placenta. The fetal adrenal gland also plays a role in estrogen production throughout fetal life. Closer to term, gonadotropin activity declines via negative feedback
• At birth, with the sudden loss of maternal and placental sex steroid contributions, the neonate experiences a resurgence of gonadotropins, and peaks or pulses may be identified for several years. Episodic sex steroid production and ovarian cysts may result.
• Estrogen, “GnRH pulse generator”, is suppressed during childhood
• With the onset of puberty, nocturnal gonadotropin secretory episodes increase, primarily LH, and in essence reflect an increase in pulse amplitude.
• As puberty progresses, wake-time gonadotropin pulses increase, and sleep-associated pulses decrease to an eventual loss of diurnal variation with more advanced puberty. Regular daytime LH pulses are followed closely by thelarche, and the achievement of a mature LH pattern seems to parallel the growth spurt
• Eventually, positive feedback mechanisms ensue, which give rise to ovarian estradiol–triggered LH surges, ovulation, and the establishment of regular menses

Question 5

Define ammenorrhoea

Answer 5

Primary amenorrhoea: lack of menses by age 15 years in a patient with appropriate development of secondary sexual characteristics, or absent menses by age 13 years and no other pubertal maturation.

Secondary amenorrhoea: lack of menses in a non-pregnant female for at least 3 cycles of her previous interval, or lack of menses for 6 months in a patient who was previously menstruating.

Question 6

What are the causes of amenorrhoea

Answer 6

• Hypogonadotropic hypogonadism: 40%
  
  • Constitutional delay
  • Functional [Chronic disease eg IBD, eating disorders, exercise]
  • Permanent [CNS tumours, infiltration, Kallmans, isolated gonadotropin deficiency]
• Hypergonadotropic hypogonadism: 35%
  
  • Chromosomal:
    • Turners syndrome 45 X0
    • Klinefelter syndrome 47 XXY
  • Disorders of sex development
    
    • Swyer Syndrome: XY pure gonadal dysgenesis
    • Congenital adrenal hyperplasia.
    • Premature ovarian insufficiency
  • Acquired
    
    • Chemotherapy / Radiation therapy from childhood cancer
    • Autoimmune gonadal failure
• Eugonadism :25%
  
  • Outflow tract anomalies [MRKH, AIS, TV septum] 20%
  • Other endocrine [PCOS, adrenal, thyroid] 5%

Question 7

What are the goals of treatment in primary amenorrhoea

Answer 7

Goals of treatment: (puberty induction)

• Develop and maintain secondary sexual characteristics
• Induce growth spurt
• Maintain bone mass, and monitoring with dexa q 5 yrs
• Protect against CVD risk
• Possibly reduce cognitive decline
• +- gonadectomy (if non functioning gonad high risk of malignancy, if functioning gonad risk of malignancy lower so gonadectomy can be delayed until 18-20 yrs)
• Address functional, sexual and psychological issues
• Fertility discussion

Question 8

What are the causes of primary ovarian insuffiency?

Answer 8

Genetic

• Turner syndrome (TS)
• Other defects in the X chromosome
• Pre-mutation FMR1 gene
• Somatic gene mutations (e.g. BPES, mutations in FOXL2 gene)
• Genetic causes of primary hypogonadism without ovarian follicle depletion (e.g. mutations in genes affecting BMP15, inhibin, CYP17, StAR, FSH receptor, Gs alpha subunit)

Autoimmune oophoritis

• Isolated
• Associated with Addison’s disease or polyglandular syndrome

Ovarian toxin

• Chemotherapy (e.g. alkylating agents, methotrexate, 6 mercaptopurine, actimomycin and adriamycin)
• Radiation (typically megavoltage irradiation [4500–5000 rads])
• Galactosaemia

Infection (e.g. mumps)

Surgery

• Oophorectomy
• Other (e.g. hysterectomy)