A 46‑year‑old woman presents with extreme fatigue, laboratory evidence of iron deficiency (low ferritin, low transferrin saturation) and a perimenopausal hormone profile (luteinizing hormone 14 IU/L, follicle‑stimulating hormone 18 IU/L, estradiol 32 pg/mL, progesterone 0.5 ng/mL, dehydroepiandrosterone sulfate 33 µg/dL); what is the appropriate evaluation and management?

Management of Iron Deficiency with Perimenopausal Symptoms in a 46-Year-Old Woman

This patient has absolute iron deficiency (ferritin 12 ng/mL, transferrin saturation 12%) causing her extreme fatigue, and she requires immediate iron repletion with oral ferrous sulfate 325 mg daily or on alternate days, along with evaluation for the source of iron loss and assessment of her perimenopausal transition. 1, 2, 3

Iron Deficiency Diagnosis and Significance

Your patient's laboratory values confirm absolute iron deficiency without inflammation:

• Ferritin 12 ng/mL is well below the 30 ng/mL threshold that defines absolute iron deficiency in patients without active inflammation 1, 4, 3
• Transferrin saturation 12% is below the 16% cut-off for iron deficiency in non-inflammatory states 1, 4
• The combination of ferritin <30 ng/mL with transferrin saturation <16% confirms true iron depletion requiring treatment 1, 3

Iron deficiency at this severity directly causes the extreme fatigue she reports. In nonanemic women with ferritin <50 ng/mL, iron supplementation reduces fatigue scores by approximately 47% compared to 29% with placebo 5. Iron deficiency impairs thyroid hormone metabolism, shifts ATP production to less efficient anaerobic pathways, and reduces expression of iron-dependent metabolic enzymes—all contributing to profound fatigue 1.

Perimenopausal Hormone Profile

Her hormone panel is consistent with early perimenopause:

• FSH 18 IU/L and LH 14 IU/L show elevation beginning to occur (perimenopause typically shows FSH >10-15 IU/L with fluctuating values) 1
• Estradiol 32 pg/mL is low, reflecting declining ovarian function 1
• Progesterone 0.5 ng/mL indicates anovulation or luteal phase insufficiency 1
• DHEAS 33 µg/dL is low for age 46 (normal range typically 35-430 µg/dL), suggesting adrenal androgen decline that accompanies perimenopause

The hypoestrogenic state in perimenopause can independently contribute to fatigue, but iron deficiency is the primary treatable cause of her symptoms 1.

Mandatory Evaluation for Blood Loss

In a 46-year-old woman, you must identify the source of iron deficiency:

Gynecologic Assessment

• Heavy menstrual bleeding is the most common cause of iron deficiency in premenopausal women and becomes more prevalent during perimenopause due to anovulatory cycles 2, 3, 6
• Quantify menstrual blood loss: number of days, pad/tampon changes per day, passage of clots
• Consider pelvic ultrasound to evaluate for fibroids or endometrial pathology if bleeding is heavy

Gastrointestinal Evaluation

• Bidirectional endoscopy (upper endoscopy and colonoscopy) is mandatory in postmenopausal women and should be strongly considered in perimenopausal women age >45 years to exclude occult gastrointestinal malignancy 1, 3, 6
• Nine percent of patients over age 65 with iron deficiency have gastrointestinal cancer; this risk begins rising after age 50 6
• Test for Helicobacter pylori (stool antigen or urea breath test) as it causes chronic gastritis and impaired iron absorption 3
• Screen for celiac disease with tissue transglutaminase IgA antibody plus total IgA, as 2-3% of iron deficiency patients have undiagnosed celiac disease 1, 3

Medication and Dietary History

• Document NSAID or aspirin use (causes occult GI blood loss) 1, 6
• Assess dietary iron intake, though borderline deficient diets alone should not preclude full GI investigation 1

Iron Repletion Strategy

First-Line: Oral Iron Therapy

Initiate oral ferrous sulfate 325 mg (65 mg elemental iron) daily or on alternate days 2, 3:

• Alternate-day dosing (every other day) improves absorption and reduces gastrointestinal side effects compared to daily dosing 4, 3
• Take on an empty stomach (1 hour before or 2 hours after meals) to maximize absorption
• Avoid taking with calcium supplements, antacids, proton pump inhibitors, or tea/coffee which impair absorption
• Common side effects include constipation, nausea, and dark stools; these occur in approximately 50% of patients and reduce adherence 3

Monitoring Response

• Recheck complete blood count and iron studies in 4-8 weeks 4, 3, 6
• Expect hemoglobin to increase by 1-2 g/dL within 4-8 weeks if treatment is effective 4, 6
• Ferritin should rise; target ferritin ≥30-45 ng/mL with transferrin saturation ≥20% in patients without inflammation 4
• If no response after 8-10 weeks, consider malabsorption, ongoing blood loss, or switch to intravenous iron 2, 3

Indications for Intravenous Iron

Switch to intravenous iron (ferric carboxymaltose, iron sucrose, or low-molecular-weight iron dextran) if 4, 2, 3:

• Intolerance to oral iron (severe GI side effects)
• Malabsorption documented (celiac disease confirmed)
• Ongoing heavy menstrual bleeding that exceeds oral replacement capacity
• Lack of hemoglobin response after 8-10 weeks of adequate oral therapy
• Patient preference for faster repletion

Intravenous iron formulations have hypersensitivity rates <1% with newer preparations 3.

Perimenopausal Symptom Management

Address the perimenopausal transition after correcting iron deficiency:

• If fatigue persists despite iron repletion to ferritin >30 ng/mL and transferrin saturation >20%, consider that hypoestrogenism contributes 1
• Low estradiol (32 pg/mL) and elevated FSH (18 IU/L) with anovulation (progesterone 0.5 ng/mL) can cause fatigue, mood changes, and vasomotor symptoms 1
• Hormonal contraception (combined oral contraceptives or levonorgestrel IUD) can regulate menstrual bleeding, reduce iron loss, and provide estrogen support if she has no contraindications
• Menopausal hormone therapy may be considered if she transitions to menopause and has bothersome vasomotor symptoms, but this decision should follow iron correction

Common Pitfalls to Avoid

• Do not attribute all fatigue to perimenopause when ferritin is 12 ng/mL—iron deficiency is the primary driver and must be corrected first 5, 2
• Do not skip GI evaluation in a 46-year-old woman, especially if she is approaching menopause when menstrual bleeding should not cause this degree of deficiency 1, 3, 6
• Do not measure iron parameters within 4 weeks of starting oral iron if you plan to recheck, as circulating iron can falsely elevate results; wait 4-8 weeks 4
• Do not continue oral iron indefinitely without monitoring response—lack of hemoglobin rise by 1-2 g/dL in 4-8 weeks indicates treatment failure requiring investigation 3, 6
• Do not assume normal ferritin means adequate iron stores in inflammatory conditions—but this patient has no evidence of inflammation, so her ferritin of 12 ng/mL is a true reflection of depleted stores 1, 4

Algorithmic Approach Summary

1. Confirm iron deficiency diagnosis: Ferritin 12 ng/mL + transferrin saturation 12% = absolute iron deficiency 1, 3
2. Initiate oral ferrous sulfate 325 mg daily or alternate-day 2, 3
3. Evaluate for blood loss source:
   • Quantify menstrual bleeding
   • Test for H. pylori and celiac disease 3
   • Perform bidirectional endoscopy if age >45-50 or if menstrual bleeding does not explain severity 1, 3, 6
4. Recheck CBC and iron studies at 4-8 weeks: Expect Hgb increase of 1-2 g/dL 3, 6
5. If no response: Switch to IV iron or investigate malabsorption/ongoing loss 2, 3
6. After iron correction: Reassess fatigue and consider perimenopausal management if symptoms persist 1