A 28-year-old woman with a history of regular menstrual cycles presents with secondary amenorrhea for 4 months. She denies pregnancy, weight loss, stress, or galactorrhea. Pelvic examination is normal. Urine pregnancy test is negative. What is the most appropriate next investigation?

Explanation

## Clinical Context This patient has secondary amenorrhea (previously regular cycles) with no clinical signs of hyperprolactinemia (no galactorrhea, no visual symptoms) and no obvious stressors or weight changes. The workup for secondary amenorrhea follows a systematic approach based on prevalence and reversibility of causes. ## Diagnostic Algorithm for Secondary Amenorrhea ```mermaid flowchart TD A[Secondary Amenorrhea]:::outcome --> B[Exclude pregnancy]:::action B --> C[Assess for signs of hyperandrogenism<br/>or hyperprolactinemia]:::decision C -->|Present| D[Specific hormonal tests]:::action C -->|Absent| E[Check TSH + Free T4]:::action E --> F{Normal thyroid?}:::decision F -->|No| G[Treat thyroid disorder]:::action F -->|Yes| H[Serum prolactin]:::action H --> I{Elevated prolactin?}:::decision I -->|Yes| J[MRI pituitary]:::action I -->|No| K[FSH/LH + Pelvic US]:::action ``` ## Investigation of Choice: Serum TSH and Free T4 **High-Yield:** Thyroid dysfunction (both hypothyroidism and hyperthyroidism) is one of the most common reversible causes of secondary amenorrhea. TSH screening is cost-effective, non-invasive, and should be performed early in all cases of secondary amenorrhea. **Key Point:** The workup sequence for secondary amenorrhea (in absence of obvious signs): 1. **Exclude pregnancy** (urine/serum β-hCG) — already done ✓ 2. **TSH + Free T4** — screen for thyroid dysfunction (most common endocrine cause after pregnancy) 3. **Serum prolactin** — if TSH normal 4. **FSH/LH + pelvic ultrasound** — if prolactin normal **Clinical Pearl:** Hypothyroidism causes amenorrhea through elevated TRH → elevated prolactin (secondary hyperprolactinemia). Hyperthyroidism can suppress GnRH. Both are reversible with treatment. ## Why TSH Before Prolactin? | Investigation | Rationale | Timing | |---|---|---| | **TSH + Free T4** | Screens for thyroid dysfunction; common reversible cause; cost-effective | **First** | | Serum prolactin | Indicated if TSH normal; more specific but less common cause | Second | | FSH/LH + Pelvic US | Assesses ovarian reserve and structural pathology | Third | | Pelvic ultrasound alone | Not first-line; does not diagnose functional amenorrhea | Not indicated initially | **Mnemonic for secondary amenorrhea causes:** **PTHYPO** — Pregnancy, Thyroid, Hyperprolactinemia, Hypothalamic (stress/weight loss), Polycystic ovary syndrome, Ovarian failure.