Chapter Notes: Primary amenorrhoea

Introduction

• Menstruation is the final step in puberty for most girls, marking sexual maturity.
• It results from a series of events starting with hypothalamic maturation in late childhood.
• Primary amenorrhoea occurs when there is a failure in this process, affecting organs involved in puberty.
• Managing primary amenorrhoea requires understanding female embryology, pubertal endocrinology, and a holistic assessment of the adolescent girl.

Definition

• Primary amenorrhoea is the absence of menstruation in a girl who has not yet menstruated.
• It is challenging to define due to the wide age range (10-18 years) when menstruation typically begins.
• It should be considered in the context of overall pubertal development, not as an isolated event.
• Investigation is recommended if no secondary sexual characteristics develop by age 14 or if menstruation does not occur within 2 years of secondary sexual characteristic development.
• Any parental concern about delayed puberty or menstruation warrants investigation, often due to comparisons with siblings.
• Confirming normality through investigation is as important as diagnosing abnormalities.
• The term "delayed puberty" is more practical than primary amenorrhoea, as it covers the entire process of reaching sexual maturity.

Normal Puberty

• Puberty is the period when a person becomes capable of reproduction, involving physical and psychological changes.
• It includes five secondary sexual characteristics in girls: breast development, pubic hair, axillary hair, growth spurt, and menstruation, followed later by ovulation.
• Breast development (Tanner classification, 5 stages) starts around age 9 and takes about 5 years to complete; absence by age 13 is unusual.
• Pubic hair development (5 stages) occurs alongside breast development.
• Axillary hair (3 stages) develops later, around age 13.
• The growth spurt occurs between ages 10-14, with peak height velocity around 12.1 years.
• Menstruation begins in 95% of UK girls by age 13, though delays up to age 16 are considered normal.

Investigative pathway for a patient with normal sexual characteristics
Investigative pathway for a patient with no secondary sexual characteristics

• Pubertal changes result from endocrine maturation, with low gonadotrophin levels in childhood increasing as the hypothalamus matures, releasing gonadotrophin-releasing hormone (GnRH).
• Ovarian stimulation begins around age 8.5, producing oestradiol, which drives breast development and menstruation.
• Adrenarche (rise in androgens like DHEA and DHEAS) starts around age 6, peaks by age 12, and triggers pubic and axillary hair growth.

Aetiology of Primary Amenorrhoea

• Causes are classified based on the presence or absence of secondary sexual characteristics and the presence of heterosexual development.

Classification of Primary Amenorrhoea

Secondary Sexual Characteristics Normal

Imperforate Hymen

• Presents in early childhood with a bulging hymen due to mucus accumulation (mucocele) or at puberty with cyclical abdominal pain from menstrual blood accumulation (haematocolpos).
• Rarely, blood accumulates in the uterus (haematometra) due to its muscular nature.
• Large masses may cause difficulty with urination or defecation.
• Examination shows an abdominal swelling and a tense, bluish hymen at the introitus.

Transverse Vaginal Septum

• Caused by failure of vaginal canalization, leading to separation of upper and lower vagina.
• Presents with cyclical abdominal pain due to haematocolpos.
• Examination shows a blind-ending, pink vagina (not bluish), with possible hymenal remnants.
• May occur at lower, middle, or upper third of the vagina; significant separation may result in no introital swelling, detectable by rectal exam.
• Requires careful assessment before management, unlike imperforate hymen.

Absent Vagina and Functioning Uterus

• Rare condition where the uterine body develops normally, but the cervix and upper vagina do not.
• Presents with cyclical abdominal pain but no pelvic mass due to absent vagina.
• Retrograde menstruation may lead to endometriosis and pelvic adhesions.

Absent Vagina and Non Functioning Uterus

• Second most common cause of primary amenorrhoea (after Turner syndrome), known as Meyer-Rokitansky-Kuster-Hauser (MRKH) syndrome.
• Normal secondary sexual characteristics due to intact ovarian function.
• Examination shows normal female external genitalia but a blind-ending vaginal dimple (≤1.5 cm deep).
• Uterine development is rudimentary, often with small uterine remnants on pelvic side walls.
• 40% of patients have renal anomalies (15% major, e.g., absent kidney), and skeletal abnormalities are common.

XY Female

• Caused by failure of testicular development, enzymatic failure to produce testosterone, or androgen receptor defects (androgen insensitivity).
• In androgen insensitivity, a non-functional androgen receptor prevents masculinization, resulting in a female phenotype with normal breast development (due to peripheral androgen-to-oestrogen conversion).
• Pubic hair is scanty, vulva is normal, but the vagina is short, and uterus/tubes are absent.
• Testes are usually in the lower abdomen or occasionally in hernial sacs, detected during childhood surgery.

Resistant Ovary Syndrome

• Rare condition with elevated gonadotrophins despite normal ovarian tissue.
• Some secondary sexual characteristics develop, but oestrogen levels are insufficient for menstruation.
• Believed to result from absent or malfunctioning FSH receptors in ovarian follicles.

Constitutional Delay

• Normal secondary sexual characteristics with no anatomical or endocrine abnormalities.
• Caused by immature pulsatile GnRH release, confirmed by 24-hour serial sampling.
• Patients eventually menstruate spontaneously as hypothalamic maturation progresses.

Secondary Sexual Characteristics Absent (Normal Height)

Isolated GnRH Deficiency (The Olfactogenital Syndrome, Kallman Syndrome)

• Hypothalamus fails to produce GnRH, causing hypogonadotrophic hypogonadism.
• Pituitary responds normally to exogenous GnRH.
• Caused by maldevelopment of hypothalamic arcuate nucleus neurones, derived from the olfactory bulb.
• Some patients have anosmia (Kallman syndrome) due to mutations in KAL1 or FGFR1 genes, affecting olfactory and GnRH-secreting neurones.

Weight Loss/Anorexia

• More common in secondary amenorrhoea but can occur prepubertally, preventing GnRH activation.
• Results in persistent hypogonadotrophic state; growth spurt is unaffected, but secondary sexual characteristics are absent.

Excessive Exercise

• Excessive exercise (e.g., in ballet dancers, athletes, gymnasts) reduces body fat, disrupting puberty.
• Body weight may remain normal due to muscle mass, so weight alone is not a reliable indicator.
• May lead to amenorrhoea or progress to anorexia nervosa.

Hyperprolactinaemia

• Rare cause of primary amenorrhoea, more common in secondary amenorrhoea.
• May be due to a prolactinoma or idiopathic; imaging may reveal pituitary anomalies.

Gonadal Agenesis

• Complete failure of gonad development in 46XX or 46XY individuals.
• In 46XX, caused by autosomal recessive genes (location unclear); phenotype is female regardless of genotype.
• In 46XY or 45X/46XY, absence of testicular determining factor or its receptor prevents testicular development.
• No androgen or Müllerian inhibitor is produced, leading to regression of Wolffian structures and persistence of Müllerian structures.
• Menstruation occurs with oestrogen administration; external genitalia are female, and height is normal.
• In 46XY, lack of androgen/oestrogen delays epiphyseal closure, potentially causing excessive height.

Ovarian Failure

• Caused by chemotherapy or radiotherapy for childhood malignancies, leading to ovarian destruction.

Galactosaemia

• Inborn error of galactose metabolism due to deficiency of galactose-1-phosphate uridyl transferase.
• Accumulation of galactose metabolites causes ovarian cellular destruction, possibly via apoptosis, leading to hypogonadotrophic hypogonadism.

Gonadal Dysgenesis

• Abnormal gonad formation, most commonly Turner syndrome (45X karyotype, missing X or Y chromosome).
• Other causes include mosaics (e.g., 45X/46XX) or X chromosome deletions affecting gonadal development.
• In Turner syndrome, ovaries develop normally until 20 weeks gestation, but massive atresia occurs later, leaving stromal ovaries unable to produce oestrogen.
• Normal female phenotype and internal genitalia, but short stature due to loss of height genes on the X chromosome.
• In mosaics, severity depends on the proportion of 45X cells.
• In XY individuals, dysgenetic gonads with enzymatic failure prevent testosterone production, leading to Müllerian atrophy and female external phenotype with a short vagina.

Secondary Sexual Characteristics Absent (Short Stature)

Congenital Infection

• Hydrocephalus from childhood/neonatal infections damages the hypothalamus, impairing GnRH secretion and causing hypogonadotrophic hypogonadism.

Trauma

• Skull base trauma may impair hypothalamic GnRH secretion, preventing puberty.

Empty Sella Syndrome

• Rare condition with congenital absence of part or all of the pituitary gland, leading to gonadotrophin deficiency and absent secondary sexual characteristics.

Tumours

• Pituitary tumours, such as craniopharyngioma, destroy the gland, causing hypogonadotrophic hypogonadism.
• Patients often present on maintenance therapy for other hormonal deficiencies.

Turner Syndrome

• 45X karyotype causes short stature and ovarian failure.
• Patients present in teenage years due to absent secondary sexual characteristics or are referred from growth clinics for puberty induction.
• Improving height is challenging.

Heterosexual Development

Congenital Adrenal Hyperplasia

• Caused by enzyme deficiency in adrenal steroid synthesis (see Chapter 34), requiring steroid replacement.
• Poor compliance with steroid therapy delays puberty, necessitating strict control for normal pubertal development.

Androgen-Secreting Tumours

• Rare ovarian tumours (e.g., arrhenoblastoma) produce excessive androgens, causing virilization.
• Tumour removal resolves the issue.

5α-Reductase Deficiency

• XY individuals with enzyme deficiency cannot convert testosterone to 5-hydroxytestosterone, required for male external genitalia development.
• Results in female external genitalia, normal male internal genitalia, and amenorrhoea due to Müllerian agenesis.

True Hermaphrodite

• Presence of both ovarian and testicular tissue, either separately or within the same gonad.
• Causes intersex issues at birth and amenorrhoea at puberty due to androgen production disrupting the menstrual cycle.

Absent Müllerian Inhibitor

• Rare condition in XY individuals where lack of Müllerian-inhibitory substance leads to persistence of Müllerian and Wolffian structures.
• Results in dual internal genitalia and amenorrhoea.

Evaluation and Management

• Constitutional delay is the most common cause, but serious conditions must be excluded first.
• Take a detailed history and examination, focusing on secondary sexual characteristics (Tanner staging) and height.

Normal Secondary Sexual Characteristics

• Suggests possible outflow tract obstruction, the most common cause in this group.
• Avoid pelvic exams in adolescents; use pelvic ultrasound to assess anatomy.
• If ultrasound is inconclusive, use MRI or CT.
• If uterus is absent, perform karyotype:
  • 46XX suggests MRKH syndrome.
  • 46XY indicates XY female.
• If uterus is present with haematocolpos/haematometra, consider reconstructive surgery.
• If pelvic anatomy is normal, check gonadotrophin and prolactin levels:
  • Normal levels suggest constitutional delay.
  • Elevated LH/FSH ratio may indicate polycystic ovaries.
  • Elevated gonadotrophins suggest resistant ovary syndrome.
  • Elevated prolactin suggests prolactinoma.

Management

• Absent uterus (e.g., MRKH syndrome) requires psychological counselling and management in a specialized centre with psychosexual and gynaecological expertise.
• Address future sexual activity and infertility concerns; vaginal creation possible with dilators (85% success) or surgery.
• For XY females, counsel about 30% malignancy risk in gonads; perform gonadectomy after counselling, timing based on patient-clinician relationship.
• Share karyotype information when appropriate, based on patient readiness.
• For imperforate hymen, a cruciate incision allows drainage of menstrual blood.
• Transverse vaginal septae require complex reconstructive surgery for functional vagina.
• For constitutional delay with complete secondary sexual characteristics, annual review is sufficient; a single cycle of oral contraceptive pill may reassure by inducing menstruation.
• Resistant ovary syndrome requires ovarian biopsy to confirm absent oocytes.
• Elevated prolactin warrants pituitary imaging (CT/MRI) for microadenoma; treat with bromocriptine.

Absence of Secondary Sexual Characteristics

• Assess height:
  • Normal height with low gonadotrophins indicates hypogonadotrophic hypogonadism.
  • Normal height with high gonadotrophins prompts karyotyping:
    • 46XX: Premature ovarian failure, resistant ovary syndrome, or gonadal agenesis.
    • 46XY: Gonadal agenesis or testicular enzymatic failure.
  • Short stature with low gonadotrophins suggests intracranial lesion.
  • Short stature with high gonadotrophins and karyotyping usually indicates Turner syndrome or mosaic.

Management

• For hypogonadotrophic hypogonadism, treat underlying causes (e.g., weight restoration) or use hormone replacement therapy to induce secondary sexual characteristics.
• Inform patients of infertility; ovulation induction is possible later with fertility treatments.
• Hormone replacement involves oestrogen alone for 2 years, then gradual progestogen introduction over 2-3 years to mimic normal breast development.
• Avoid high oestrogen doses to prevent abnormal breast growth.
• For XY dysgenesis or enzymatic failure, perform gonadectomy to prevent malignancy.
• Consider chronic medical illnesses that delay puberty in differential diagnosis.