Primary amenorrhoea

Question 1

What is primary amenorrhoea defined as?

Answer 1

Primary menorrhoea is defined as not starting menstruation:

• by 13 yrs when there is no other evidence of pubertal development
• by 15 yrs when there are other signs of development (such as breast bud development)

Question 2

At what age does puberty begin in girls and how long does it last?

Answer 2

• 8-14
• takes about 4 years
• girls have their pubertal growth spurt earlier than boys

Question 3

Describe the stages of puberty in order in girls?

Answer 3

development of breast buds -> pubic hair -> menstrual periods

-menstrual periods usually begin about 2 years from the start of puberty

Question 4

What does hypogonadism refer to?

Answer 4

• hypoganadism refers to the lack of sex hormones, oestrogen and testosterone, that usually rise before and during puberty
• this causes a delay in puberty

Question 5

What can hypogonadism be due to?

Answer 5

-hypogonadism 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 (testes and ovaries

Question 6

Describe how a deficiency of LH and FSH lead to a deficiency in sex hormones(oestrogen) in hypogonadotropic gonadism

Answer 6

• LH and FSH are gonadotrophins produced by the anterior pituitary gland in response to GnRh from the hypothalamus
• since no gonadotrophins are stimulating the ovaries, they do not respond by producing oestrogen.
• therefore ‘hypogonadotopism’ causes hypogonasim’

Question 7

What causes hypogandotopic hypognadism?

Answer 7

caused by abnormal function of hypothalamus or pituitary gland which could be due to:

• Hypopituitarism (under production of pituitary hormones)
• Damage to hypothalamus or pituitary, e.g radiotherapy or surgery for cancer
• significant chronic conditions can temp delay puberty, e.g CF or IBD
• Excessive exercise or diet
• Constitutional delay in growth and development
• endocrine disorders, e.g GHD, hypothryroidsm, cushing’s or hyperprolactinaemia
• kallman syndrome

Question 8

What is hypergonadotropic hypoganadism?

Answer 8

-it is where the gonads(ovaries) fail to respond to stimulation from the gonadotropins (LH and FSH)

Question 9

Why is there an increase in LH and FSH in hypergonadotropic hypogonadism?

Answer 9

• as ovaries are not stimulated by the hormones, oestrogen is not produced
• therefore no negative feedback from oestrogen so the anterior pituitary produces increasing amounts of LH and FSH

Question 10

What can cause hypergonadotropic hypogonadism?

Answer 10

• previous damage to the ovaries, e.g torsion, cancer or infections like mumps
• congenital absense of ovaries
• Turner’s syndrome

Question 11

How does Kallman syndrome affect puberty?

Answer 11

Kallman syndrome is a genetic condition causing hypogonadotropic gonadism, with failure to start puberty.
-it is also associated with reduced or absent sense of smell (anosmia)

Question 12

What is congenital adrenal hyperplasia caused by?

Answer 12

• 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
• female patients can present later in childhood or at puberty with primary amenorrhoea

Question 13

What is androgen insensitivity syndrome?

Answer 13

• 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
• this results in the female phenotype, other than the internal pelvic organs
• patients have normal external genatalia and breast tissue but internally there are testes in the abdomen/inguinal canal and absent female internal organs
• so these patients who believe can prevent with absent periods but are genetically male

Question 14

How can structural pathology in the pelvic organs prevent menstruation?

Answer 14

Structural pathology that can cause primary amenorrhoea include:

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

Question 15

What are the aims of assessment for primary amenorrhoea?

Answer 15

-Assessment aims to look for evidence of puberty and to assess for possible underlying causes

Question 16

What are the initial investigations for primary amenorrhoea?

Answer 16

• FBC and ferritin for anaemia
• U&E for CKD
• Anti-TTG or anti-EMA for coeliac disease

Question 17

What are the hormonal blood tests for primary amenorrhoea?

Answer 17

• FSH and LH
• TFT
• Insulin-like growth factor I -> used to screen for GH deficiency
• Prolactin
• Testosterone -> raised in POS, AIS and CAH

Question 18

What genetic testing might be used for primary amenorrhoea?

Answer 18

-Turner’s syndrome

Question 19

What imaging can be useful for primary amenorrhoea?

Answer 19

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

Question 20

What does the management of primary amenorrhoea involve?

Answer 20

• Management of primary amenorrhoea involves establishing and treating the underlying cause.
• Where necessary, replacement hormones can induce menstruation and improve symptoms

Question 21

What is the management for primary amenorrhoea in patients with constitutional delay in growth and development?

Answer 21

Patients with constitutional delay in growth and development may only require reassurance and observation

Question 22

What is the management for primary amenorrhoea caused by stress or low body weight secondary to diet or exercise?

Answer 22

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.

Question 23

What is the management for primary amenorrhoea in patients with hypogonadotropic hypogonadism?

Answer 23

• 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 24

What is the management for primary amenorrhoea in patients with an ovarian cause?

Answer 24

-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.

Question 25

what is the genotype of androgen insensitivity syndrome?

Answer 25

46XY

Question 26

An 18-year-old girl attended her routine appointment at the hospital. At age 1, she had surgery to remove bilateral abdominal masses, which her parents noticed.

At 14, she had not had her first menstruation, and Tanner’s staging was 1.
She was started on medical treatment, and during her recent follow-up, her Tanner staging was assessed as stage 2.

Given the likely diagnosis, what is the genotype?

A. 45X0

B. 46XX

C. 46XY

D. 47XX

E. 47XXY

Answer 26

C. 46XY

Primary amenorrhoea, little or no axillary and pubic hair, elevated testosterone → androgen insensitivity syndrome
Important for meLess important
The condition presented is androgen insensitivity syndrome; the child is genotypically male but presents as female phenotypically. This is due to a mutation in the gene encoding the androgen receptor causing resistance to testosterone.

The abdominal masses removed were undescended testes.

The absence of menstruation is contributed by the lack of development of internal female genitalia due to the anti-Mullerian hormone produced by the testes. She was started on estrogen hormone replacement to help with physical female characteristics development, which subsequently led to breast development described as Tanner stage 2.

Question 27

how is androgen insensitivity syndrome treated?

Answer 27

-buccal smear or chromosomal analysis to reveal 46XY genotype

-after puberty, testosterone concentrations are in the high-normal to slightly elevated reference range for postpubertal boys

Question 28

how is androgen insensitivity syndrome diagnosed?

Answer 28

1. Counselling - raise the child as female
2. bilateral orchidectomy (increased risk of testicular cancer due to undescended testes)
3. oestrogen therapy

Question 29

A 17-year-old comes to your clinic, concerned that she has not yet started her periods although most of her friends have. She is 150 cm tall and 45 kg in weight. She reports the development of pubic hair since the age of 14 and has normal breast development. On speculum examination, you are unable to visualise the cervix and the patient finds the examination too uncomfortable to tolerate further. Serum hormone screening reveals no gross abnormality. What management would you suggest?

A. Refer to a gynaecologist

B. Reassess in one year

C. Advise her to increase her calorie intake, check her hormone levels and reassess in two months.

D. Serum hormone screening

E. Refer to endocrinologist

Answer 29

It is important to consider causes of amenorrhoea, which can be broken down as follows:

Primary amenorrhoea: a woman has never had a period

A woman who has previously had periods now hasn’t for (often quoted as lack of menses for least 6 months in women with previously normal periods, or for 12 months in women with previous oligomenorrhoea)

Question 30

what are the causes of primary amenhorrea?

Answer 30

-gonadal dysgenesis (e.g. Turner’s syndrome) - the most common causes
-testicular feminisation
-congenital malformations of the genital tract
-functional hypothalamic amenorrhoea (e.g. secondary to anorexia)
-congenital adrenal hyperplasia
-imperforate hymen

Question 31

what is the most common cause of primary amenhorrea?

Answer 31

Turner’s syndrome

Question 32

what is the 2nd most common cause of primary amenhorrea?

Answer 32

Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome (mullarian agenesis)

Question 33

what is mullerian duct responsible for

Answer 33

development of uterus, cervix & upper 2/3rds of vagina

Question 34

what is genotype in Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome (mullarian agenesis)

Answer 34

46xx

Question 35

what are the hormones like in Turner’s syndrome

Answer 35

High LH, FSH, low oestradiol (streak ovaries: primary ovarian failure)
-Primary ovarian failure develops because the absence of a second normal X chromosome leads to the loss of follicles and therefore loss of normal oestrogen and progesterone production.
-FSH levels at menopause are ≥30 IU/L.

Such females will require oestrogen (and later progesterone) therapy ideally at age 11-12 to maximise growth.

Question 36

what endocrine test should be measured in Turner’s syndrome?

Answer 36

Hypothyroidism is associated with Turner’s syndrome, so thyroid function should be checked.

Question 37

what endocrine problem is associated with Down’s syndrome?

Answer 37

Patients with Down’s syndrome are at an increased risk of both hyper and hypothyroidism.
-However, the risk of hypothyroidism is much greater