Primary Amenorrhoea Station

Presenting Complaint - Primary Amenorrhoea

History of Presenting Complaint:

• Secondary sexual characteristics - she denies breast development, but reports having axillary and pubic hair.
• Normal growth
• She is not sexually active (very important to rule out pregnancy!)
• No significant weight loss or extreme exercise regimens (hypothalamic functional amenorrhoea)
• She reports symptoms suggestive of hypoestrogenism for the past 3 months (primary ovarian insufficiency (POI)):
  • Hot flushes
  • Night sweats
• She denies the following symptoms:
  • Reduced/loss of sense of smell (Kallman syndrome)
  • Headaches and vision changes (pituitary gland tumour)
  • Galactorrhoea (hyperprolactinaemia)
  • Excessive hair growth and acne (PCOS)
  • Heat/cold intolerance, changes to weight, changes to bowel habits, hair or skin changes, sweating, palpitations, anxiety (thyroid dysfunction)
  • Abdominal pain or cramping (imperforate hymen)
  • Systemic symptoms e.g. unintentional weight loss, fatigue, changes to appetite, night sweats

Previous Medical History

• Otherwise healthy with no significant past medical history

• No recent illnesses or surgery

Drug History

• Nil regular

Allergies

• NKDA

Family History

• Normal age of menarche in mother and aunts
• No menstrual, gynaecological, or pubertal problems in the family

Social History

• Enjoys going to school every day

• Lives with her mum, dad, and younger brother

• Has never smoked, drunk alcohol, or taken recreational drugs

ICE

• Ideas: “Could this be caused by some kind of genetic condition?”

• Concerns: Hannah’s mother is worried that this condition could be serious and may affect Hannah’s fertility down the line

• Expectations: To get the correct diagnosis

Examination Findings:

• Height and weight are appropriate for her age (short stature could be a sign of Turner’s syndrome)
• Normal BMI (low BMI can delay menarche and may suggest functional hypothalamic amenorrhoea or chronic illness/systemic disease)
• Tanner staging reveals Tanner staging 1 for breast development and Tanner stage 4 for pubic hair (suggests hypoestrogenism and normal androgen levels)
• Examination of the external genitalia is normal (ambiguous genitalia may suggest a disorder of sexual differentiation, enlarged clitoris may suggest hyperandrogenism, outflow obstruction may suggest imperforate hymen or transverse vaginal septum, absence of uterus and vagina may suggest Mullerian agenesis)

Most Likely Differentials:

• POI (due to symptoms associated with hypoestrogenism e.g. lack of breast development, hot flushes, night sweats)
• PCOS
• Turner’s Syndrome

Management

• Bedside:
  • Pregnancy Test (the first thing you need to do is to rule out the possibility of pregnancy, even if the patient denies it, as it’s not a diagnosis you would want to miss!)
• Lab:
  • FBC, U&Es, LFTs, CRP for baseline
  • Hormonal Assay (prolactin, TFTs, LH, FSH, oestrogen, testosterone)
• Imaging:
  • Pelvic Ultrasound (to evaluate anatomy and check for ovarian cysts as part of PCOS diagnostic workup)
  • MRI of the brain (if abnormal neurological findings or elevated prolactin levels to rule out possibility of masses or tumours within the pituitary gland or hypothalamus, or any infiltrative diseases)

1. What is primary amenorrhoea?

• No menarche by age 13 in absence of secondary sex characteristics OR
• No menarche by age 15 regardless of secondary sex characteristics

Menarche = first ever period in a woman’s life

2. What are secondary sex characteristics?

• Physical traits that develop during puberty in response to hormonal changes, particularly androgens (e.g. testosterone in males) and oestrogens (e.g. oestradiol in females).
• Examples of secondary sex characteristics in females include the development of breasts (thelarche), growth of pubic and axillary hair (adrenarche), widening of hips, and changes in body fat distribution, with more fat deposition around the hips and breasts.
• Timeline of secondary sex characteristic development:
  • Thelarche (9-11 years old) -> Adrenarche (10-11) -> Menarche (12-13)
  • A girl should therefore have development of secondary sex characteristics prior to menarche

3. What is required for normal menstruation to occur?

In order for normal menstruation to occur, 2 things must be present and functioning:

• • Hormones of the HPO (hypothalamic-pituitary-ovarian) axis
  • All relevant anatomy

The hypothalamus releases GnRH (gonadotropin releasing hormone) -> stimulates anterior pituitary gland to release the gonadotropins FSH and LH -> stimulates ovaries to release the female sex hormones oestrogen and progesterone -> endometrial proliferation and stabilisation -> menses

4. What are the causes of primary amenorrhoea?

Primary amenorrhoea can be caused by multiple factors that affect the HPO axis. A useful way to understand the different causes of primary amenorrhoea is to think about which part of the HPO axis is affected:

• Hypothalamic Dysfunction:
  • Functional hypothalamic amenorrhoea
  • Kallman syndrome
  • Constitutional delay of puberty
  • Significant chronic conditions/systemic illnesses e.g. Type 1 diabetes, coeliac disease, IBD, cystic fibrosis etc.
  • Injury e.g. by radiotherapy, traumatic brain injury
  • Infiltrative diseases e.g. sarcoidosis, hemochromatosis
• Pituitary Gland Dysfunction:
  • Hypopituitarism (i.e. underproduction of pituitary hormones)
  • Hyperprolactinaemia secondary to:
    • Prolactinomas (headache, vision problems)
    • Medications e.g. antipsychotics, tricyclic antidepressants, metoclopramide
    • Hypothyroidism (↑TRH -> ↑Prolactin)
  • Infection e.g. encephalitis, meningitis (resulting in damage to the pituitary gland)
  • Pituitary gland tumour e.g. pituitary adenoma, craniopharyngioma
• Ovarian Dysfunction:
  • Gonadal dysgenesis (gonads fail to form correctly and do not secrete sex hormones):
    • Turner’s syndrome
    • 46, XX gonadal dysgenesis
    • Sywer syndrome
  • POF (premature ovarian failure)/POI (primary ovarian insufficiency)
  • PCOS
• Uterine/Vaginal Aetiologies:
  • Müllerian agenesis (Mayer–Rokitansky–Küster–Hauser syndrome)
  • Vaginal outflow obstruction
    • Transverse vaginal septum
    • Imperforate hymen
  • Vaginal agenesis
  • Female Genital Mutilation
• Other (Hormonal Aetiologies):
  • Thyroid Dysfunction – Hypothyroidism or hyperthyroidism
  • Complete AIS (Androgen Insensitivity Syndrome)
  • Congenital adrenal hyperplasia
  • Cushing’s syndrome
  • Adrenal insufficiency

5. What is premature ovarian insufficiency (POI)?

POI, also known as premature ovarian failure (POF), is a condition characterised by the loss of ovarian function before the age of 40. In women with POI, the ovaries stop functioning normally, leading to a decrease in oestrogen levels.

A commonly held misconception is that POI is considered the same as early or premature menopause. Despite both involving ovarian dysfunction and hormonal changes, they are not the same condition. In some women with POI, they may have intermittent ovarian function and occasional ovulation. This means they may get occasional periods and retain a degree of fertility, albeit significantly reduced. However, in menopause, ovarian function stops permanently, leading to a complete cessation of ovulation and hormonal production. Fertility is consequently lost and pregnancy without medical intervention cannot occur.

Aetiology

In most cases of POI, the cause is idiopathic, meaning it cannot be identified. However, POI can result from multiple factors, including autoimmune disorders, genetic abnormalities, environmental factors, chemotherapy or radiation therapy, ovarian surgery, or certain infections.

Clinical Presentation

• POI is defined as clinical menopause before the age of 40
• Often presents with features of hypoestrogenism:
  • Amenorrhoea or irregular periods (commonly presents as secondary amenorrhoea, but can present as primary amenorrhoea)
  • Hot flushes
  • Night sweats
  • Vaginal dryness
  • Mood changes
  • Decreased libido

Diagnosis

Diagnosis of POI is based on a combination of oligomenorrhoea/amenorrhoea of >4 months’ duration AND elevated FSH (>40 iu/l) on at least 2 occasions measured 4-6 weeks apart in a woman under the age of 40.

NB – If the diagnosis is POI is inconclusive, AMH (anti-mullerian hormone) levels can be tested. AMH is a marker of ovarian reserve and will therefore be low in a woman with POI. However, AMH should not be routinely used to diagnose POI.  

Imaging studies can be used to assess ovarian function and anatomy, but are not required for diagnosis.

Management

There are several aspects that need to be addressed when managing a patient with POI, including providing symptomatic relief, preserving fertility when possible, and addressing the long-term health risks associated with oestrogen deficiency.

• Lifestyle advice to promote bone health and cardiovascular well-being. This includes information on a balanced diet, regular exercise, adequate calcium and vitamin D intake, smoking cessation and avoidance of excessive alcohol intake.
• Assessment of bone mineral density with a DEXA scan should be considered at the time of diagnosis to calculate the patient’s risk of developing osteoporosis and guide management strategies.
• Hormonal Replacement Therapy (HRT) – to alleviate menopausal symptoms & reduce the long-term risk of conditions associated with hypoestrogenism e.g. cardiovascular disease, osteoporosis, and cognitive impairment.
• Fertility Preservation – women with POI can have intermittent ovarian activity and have a 5-10% chance of conceiving naturally. Assisted reproduction techniques using the woman’s own eggs (e.g. oocyte or embryo cryopreservation) are unlikely to be successful, but other techniques such as IVF using donor eggs or embryos may prove to be effective for women desiring pregnancy.
• Psychological Support - POI can have significant emotional and psychosocial impacts. Offering psychological support, counselling, and access to support groups can help individuals cope with the emotional challenges of POI.