Amenorrhoea

Amenorrhoea is the absence of menstruation, classified as primary or secondary.

Primary amenorrhoea is the absence of menarche by age fifteen in the presence of otherwise normal growth and secondary sexual characteristic development, or by age thirteen in the absence of any secondary sexual characteristic development.

Secondary amenorrhoea is the absence of menstruation for three or more consecutive months in a woman who has previously established regular menstrual cycles, or six or more months in a woman with previously irregular cycles.

The differential diagnosis is conventionally organised by the anatomical level of the reproductive axis affected (hypothalamic, pituitary, ovarian, or uterine/outflow tract). This gives a structured framework for diagnostic evaluation.

Pregnancy is the single most common cause of secondary amenorrhoea and must be excluded first in every presentation.

Classification and differential diagnosis

• Hypothalamic causes reflect suppression of pulsatile hypothalamic gonadotropin-releasing hormone secretion. They include functional hypothalamic amenorrhoea (from significant energy deficit, excessive exercise, or significant psychological stress), structural hypothalamic pathology and certain genetic conditions.
• Kallmann syndrome combines hypogonadotropic hypogonadism with anosmia, reflecting the shared embryological origin of olfactory and gonadotropin-releasing hormone neurons.
• Pituitary causes include hyperprolactinaemia, a common and readily identifiable, treatable cause, and other forms of hypopituitarism. Sheehan syndrome occurs in the postpartum context.
• Ovarian causes include polycystic ovary syndrome, among the commonest causes of secondary amenorrhoea and oligomenorrhoea, and primary ovarian insufficiency.
• Uterine and outflow tract causes include Müllerian agenesis, an important cause of primary amenorrhoea, and imperforate hymen and other obstructive anomalies.
• Asherman syndrome is an important cause of secondary amenorrhoea. Intrauterine adhesions most commonly follow previous uterine instrumentation, particularly after a pregnancy-related procedure. They produce endometrial scarring and outflow obstruction or, in more extensive cases, loss of functional endometrial tissue.

• Presentation varies with the underlying cause. Careful assessment of secondary sexual characteristic development is particularly relevant in primary amenorrhoea.
• Associated symptoms guide diagnosis: galactorrhoea suggests hyperprolactinaemia, hirsutism and acne suggest polycystic ovary syndrome, and vasomotor symptoms suggest primary ovarian insufficiency.
• Relevant history includes menstrual history, weight and exercise history, medication use, and any history of uterine instrumentation.
• Primary amenorrhoea with normal secondary sexual characteristic development but a structural genital tract abnormality on examination (including a shortened or absent vagina) suggests Müllerian agenesis.
• Primary amenorrhoea without secondary sexual characteristic development suggests a hypothalamic, pituitary, or ovarian cause of hypogonadism and needs full hormonal evaluation.
• Secondary amenorrhoea with hirsutism and acne suggests polycystic ovary syndrome. With vasomotor symptoms and other features of oestrogen deficiency it suggests primary ovarian insufficiency. With significant recent weight loss, excessive exercise, or psychological stress it suggests functional hypothalamic amenorrhoea.
• Previous uterine instrumentation, particularly a postpartum or post-miscarriage procedure, followed by amenorrhoea raises suspicion of Asherman syndrome and warrants targeted further evaluation.

• Pregnancy testing is the first-line investigation in any woman of reproductive age with secondary amenorrhoea, because the result directs all subsequent evaluation.
• Hormonal assessment includes follicle-stimulating hormone, luteinising hormone, prolactin, thyroid function and, where clinically indicated, testosterone. The biochemical pattern localises the cause.
• Elevated gonadotropins suggest an ovarian cause. Low or inappropriately normal gonadotropins suggest a hypothalamic or pituitary cause. Elevated prolactin or abnormal thyroid function suggests these respective alternative causes.
• Pelvic ultrasound assesses uterine and ovarian anatomy, including the polycystic ovarian morphology of polycystic ovary syndrome. It also confirms the presence and normal structure of the uterus, which is relevant to excluding Müllerian agenesis in primary amenorrhoea.
• Progestogen challenge testing assesses withdrawal bleeding after a course of progestogen. It was historically used to assess the adequacy of endogenous oestrogen production and outflow tract patency. It is now less central, because hormonal assessment and pelvic imaging are more direct and informative, though it remains occasionally useful in specific contexts.
• Karyotype analysis and further genetic testing are directed by the clinical presentation and initial findings. They are particularly relevant in primary amenorrhoea with delayed or absent pubertal development. The diagnostic principles are those of Turner syndrome and primary ovarian insufficiency.

• Management is directed by the underlying diagnosis identified through the structured anatomical approach: polycystic ovary syndrome, hyperprolactinaemia, primary ovarian insufficiency, or the structural anomalies covered under anomalies of the female genital tract.
• Functional hypothalamic amenorrhoea is managed by addressing the contributing factor: nutritional rehabilitation and reduction of excessive exercise, with psychological support where significant stress contributes. Normal menstrual function is generally expected to resume once energy balance and the associated hormonal disruption are corrected.
• Bone health needs attention in any woman with prolonged amenorrhoea and oestrogen deficiency, because oestrogen is essential for normal bone maintenance. Management is typically hormone replacement or, where relevant, restoration of normal endogenous oestrogen production by addressing the underlying cause.
• Asherman syndrome is managed with hysteroscopic adhesiolysis (surgical division of the intrauterine adhesions). Measures then prevent adhesion reformation, including, in some protocols, a temporary intrauterine device or balloon together with a course of oestrogen therapy to support endometrial regrowth.
• In Asherman syndrome, the prognosis for restored menstrual function and fertility relates directly to the severity and extent of the adhesions.
• Sensitive counselling about the diagnosis and its implications is important, particularly for fertility where this is a significant concern. Psychosocial support throughout diagnosis and treatment underpins management.