Primary Amenorrhoea

Question 1

What is primary amenorrhoea?

Answer 1

Primary amenorrhoea is defined as not starting menstruation:

• By 13 years when there is no other evidence of pubertal development
• By 15 years of age where there are other signs of puberty, such as breast bud development

Question 2

Briefly describe normal puberty

Answer 2

Puberty starts age 8-14 in girls and 9-15 in boys. It takes about four years from start to finish. Girls have their pubertal growth spurt earlier in puberty than boys.

In girls, puberty starts with the development of breast buds, then pubic hair, and finally menstrual periods about two years from the start of puberty.

Question 3

What is hypogonadism?

Answer 3

Hypogonadism refers to a lack of the sex hormones, oestrogen and testosterone, that normally rise before and during puberty.

Question 4

What causes hypogonadism?

Answer 4

Hypogonadism refers to a lack of the sex hormones, oestrogen and testosterone, that normally rise before and during puberty. A lack of these hormones causes a delay in puberty. The lack of sex hormones is fundamentally due to one of two reasons:

• Hypogonadotropic hypogonadism: a deficiency of LH and FSH
• Hypergonadotropic hypogonadism: a lack of response to LH and FSH by the gonads (the testes and ovaries)

Question 5

What is hypogonadotropic hypogonadism?

Answer 5

Hypogonadotropic hypogonadism involves deficiency of LH and FSH, leading to deficiency of the sex hormones (oestrogen). LH and FSH are gonadotrophins produced by the anterior pituitary gland in response to gonadotropin releasing hormone (GnRH) from the hypothalamus. Since no gonadotrophins are simulating the ovaries, they do not respond by producing sex hormones (oestrogen). Therefore, “hypogonadotropism” causes “hypogonadism”.

A deficiency of LH and FSH is the result of abnormal functioning of the hypothalamus or pituitary gland.

Question 6

What causes hypogonadotropic hypogonadism?

Answer 6

This could be due to:

• Hypopituitarism (under production of pituitary hormones)
• Damage to the hypothalamus or pituitary, for example, by radiotherapy or surgery for cancer
• Significant chronic conditions can temporarily delay puberty (e.g. cystic fibrosis or inflammatory bowel disease)
• Excessive exercise or dieting can delay the onset of menstruation in girls
• Constitutional delay in growth and development is a temporary delay in growth and puberty without underlying physical pathology
• Endocrine disorders such as growth hormone deficiency, hypothyroidism, Cushing’s or hyperprolactinaemia
• Kallman syndrome

Question 7

What is hypergonadotropic hypogonadism?

Answer 7

Hypergonadotropic hypogonadism is where the gonads fail to respond to stimulation from the gonadotrophins (LH and FSH). Without negative feedback from the sex hormones (oestrogen), the anterior pituitary produces increasing amounts of LH and FSH. Consequently, you get high gonadotrophins (“hypergonadotropic”) and low sex hormones (“hypogonadism”).

Hypergonadotropic hypogonadism is the result of abnormal functioning of the gonads.

Question 8

What causes hypergonadotropic hypogonadism?

Answer 8

This could be due to:

• Previous damage to the gonads (e.g. torsion, cancer or infections such as mumps)
• Congenital absence of the ovaries
• Turner’s syndrome (XO)

Question 9

What is Kallman Syndrome?

Answer 9

Kallman syndrome is a genetic condition causing hypogonadotrophic hypogonadism, with failure to start puberty. It is associated with a reduced or absent sense of smell (anosmia).

Question 10

What is congenital adrenal hyperplasia?

Answer 10

Congenital adrenal hyperplasia is caused by a congenital deficiency of the 21-hydroxylase enzyme. This causes underproduction of cortisol and aldosterone, and overproduction of androgens from birth. It is a genetic condition inherited in an autosomal recessive pattern. In a small number of cases, it involves a deficiency of 11-beta-hydroxylase rather than 21-hydroxylase.

In severe cases, the neonate is unwell shortly after birth, with electrolyte disturbances and hypoglycaemia. In mild cases, female patients can present later in childhood or at puberty with typical features:

• Tall for their age
• Facial hair
• Absent periods (primary amenorrhoea)
• Deep voice
• Early puberty

Question 11

What is angrogen insensitivity syndrome?

Answer 11

Androgen insensitivity syndrome is a condition where the tissues are unable to respond to androgen hormones (e.g. testosterone), so typical male sexual characteristics do not develop. It results in a female phenotype, other than the internal pelvic organs. Patients have normal female external genitalia and breast tissue. Internally there are testes in the abdomen or inguinal canal, and an absent uterus, upper vagina, fallopian tubes and ovaries.

Question 12

What structural abnormalities can cause primary amenorrhoea?

Answer 12

Structural pathology in the pelvic organs can prevent menstruation. If the ovaries are unaffected, there will be typical secondary sexual characteristics, but no menstrual periods. There may be cyclical abdominal pain as menses build up but are unable to escape through the vagina. Structural pathology that can cause primary amenorrhoea include:

• Imperforate hymen
• Transverse vaginal septae
• Vaginal agenesis
• Absent uterus
• Female genital mutilation

Question 13

What is the threshold for investigating primary amenorrhoea?

Answer 13

The threshold for initiating investigations is no evidence of pubertal changes in a girl aged 13. Investigation can also be considered when there is some evidence of puberty but no progression after two years.

Question 14

What blood tests can be ordered for primary amenorrhoea?

Answer 14

Initial investigations assess for underlying medical conditions:

• Full blood count and ferritin for anaemia
• U&E for chronic kidney disease
• Anti-TTG or anti-EMA antibodies for coeliac disease

Hormonal blood tests assess for hormonal abnormalities:

• FSH and LH will be low in hypogonadotropic hypogonadism and high in hypergonadotropic hypogonadism
• Thyroid function tests
• Insulin-like growth factor I is used as a screening test for GH deficiency
• Prolactin is raised in hyperprolactinaemia
• Testosterone is raised in polycystic ovarian syndrome, androgen insensitivity syndrome and congenital adrenal hyperplasia

Question 15

What genetic testing can be ordered for primary amenorrhoea?

Answer 15

Genetic testing with a microarray test to assess for underlying genetic conditions e.g. Turner’s syndrome (XO).

Question 16

What imaging can be ordered for primary amenorrhoea?

Answer 16

Imaging can be useful:

• Xray of the wrist to assess bone age and inform a diagnosis of constitutional delay
• Pelvic ultrasound to assess the ovaries and other pelvic organs
• MRI of the brain to look for pituitary pathology and assess the olfactory bulbs in possible Kallman syndrome

Question 17

Briefly describe the management of primary amenorrhoea

Answer 17

Management of primary amenorrhoea involves establishing and treating the underlying cause. Where necessary, replacement hormones can induce menstruation and improve symptoms. Patients with constitutional delay in growth and development may only require reassurance and observation.

Where the cause is due to stress or low body weight secondary to diet and exercise, treatment involves a reduction in stress, cognitive behavioural therapy and healthy weight gain.

Where the cause is due to an underlying chronic or endocrine condition, management involves optimising treatment for that condition.

Question 18

Briefly describe the management of primary amenorrhoea due to hypogonadotrophic hypogonadism

Answer 18

In patients with hypogonadotrophic hypogonadism, such as hypopituitarism or Kallman syndrome, treatment with pulsatile GnRH can be used to induce ovulation and menstruation. This has the potential to induce fertility. Alternatively, where pregnancy is not wanted, replacement sex hormones in the form of the combined contraceptive pill may be used to induce regular menstruation and prevent the symptoms of oestrogen deficiency.

Question 19

Briefly describe the management of primary amenorrhoea due to ovarian causes

Answer 19

In patients with an ovarian cause of amenorrhoea, such as polycystic ovarian syndrome, damage to the ovaries or absence of the ovaries, the combined contraceptive pill may be used to induce regular menstruation and prevent the symptoms of oestrogen deficiency.