What is the recommended diagnostic approach for a patient with PCOS, chronic fatigue, recent EBV infection, night sweats, and cold-induced circulation concerns, currently on Ozempic (semaglutide) and Sertraline?

Diagnostic Workup for 21-Year-Old with PCOS, Chronic Fatigue, Recent EBV, Night Sweats, and Circulation Concerns

This patient requires comprehensive hormonal assessment with morning TSH, free T4, cortisol, ACTH, FSH, LH, and estradiol, along with targeted evaluation for chronic active EBV infection and exclusion of lymphoproliferative disorders given the constellation of night sweats, fatigue, and recent EBV infection. 1

Primary Hormonal Evaluation

The core diagnostic approach must begin with morning (8 AM) blood tests to assess for endocrine causes of fatigue and associated symptoms:

• Thyroid function testing (TSH and free T4) is essential, as hypothyroidism causes fatigue in 66% of cases and commonly presents with low libido 1
• Morning cortisol and ACTH (drawn at 8 AM) to evaluate for adrenal insufficiency, which presents with fatigue in the majority of patients 1
• FSH, LH, and estradiol to identify hypogonadism, which commonly presents with both fatigue and decreased libido in premenopausal women 1
• Complete metabolic panel including electrolytes, as adrenal insufficiency can present with hyponatremia 1

Critical pitfall: Never start thyroid hormone replacement before addressing adrenal insufficiency, as this can precipitate adrenal crisis 1. If cortisol is 3-15 μg/dL, proceed with ACTH stimulation testing 1.

PCOS-Specific Metabolic Assessment

Given the established PCOS diagnosis and current Ozempic therapy:

• Fasting glucose and HbA1c to monitor glycemic control, as GLP-1 receptor agonists like semaglutide significantly improve insulin resistance in PCOS patients 2, 3
• Lipid panel to assess cardiovascular risk, which is elevated in PCOS 2
• C-reactive protein (CRP) as an inflammatory marker, which improves with semaglutide therapy in PCOS 2
• Testosterone levels to assess hyperandrogenism status 4

Evaluation for Chronic Active EBV Infection

The combination of chronic fatigue, night sweats, and recent EBV infection warrants specific evaluation for chronic active EBV (CAEBV):

• EBV serology including VCA-IgG (typically ≥1:640) and EA-IgG (typically ≥1:160) to assess for elevated antibody titers consistent with CAEBV 5
• Quantitative EBV PCR on peripheral blood mononuclear cells, as more than 10^2.5 copies/mg DNA are generally detected in CAEBV 5
• Complete blood count with differential to evaluate for cytopenias or lymphocytosis 5

CAEBV presents with persistent or intermittent fever, lymphadenopathy, hepatosplenomegaly, and chronic debilitating fatigue 5. Night sweats are a recognized symptom of this condition 5.

Lymphoproliferative Disorder Screening

Night sweats combined with fatigue and recent EBV infection necessitate exclusion of lymphoproliferative disorders:

• Lactate dehydrogenase (LDH) as an elevated level suggests lymphoma or other lymphoproliferative processes 5
• β2-microglobulin for prognostic assessment if lymphoproliferative disorder is suspected 5
• Erythrocyte sedimentation rate (ESR) as a non-specific inflammatory marker 5

Key consideration: Night sweats are a B symptom in lymphoma classification (defined as drenching night sweats) 5. While CAEBV can progress to T-cell or NK-cell lymphoproliferative disorders during its course 5, the presence of night sweats warrants careful evaluation.

Peripheral Vascular Assessment

The history of cold-induced circulation concerns in great toes with prior non-ischemic frostbite requires:

• Physical examination documenting pulse quality, capillary refill, and any color changes with cold exposure
• Consider Raynaud's phenomenon evaluation if symptoms suggest vasospastic disorder, though this is less likely given the frostbite history

This is likely a sequela of previous frostbite rather than active vasculitis, but document baseline vascular status.

Imaging Considerations

If multiple pituitary hormone deficiencies are identified on initial hormonal testing:

• MRI brain with pituitary cuts to evaluate for hypophysitis or other pituitary pathology 1

If lymphadenopathy is detected on physical examination or if CAEBV is confirmed:

• Ultrasound of palpable lymph nodes as initial imaging 5
• CT chest/abdomen/pelvis if persistent lymphadenopathy or concerning features develop 5

Medication Considerations

Ozempic (semaglutide) is appropriate for this patient's PCOS management, as recent evidence demonstrates:

• Significant weight loss (6-11.5 kg over 3-6 months) in obese PCOS patients 2, 3
• Improved insulin resistance and HOMA-IR 2, 3
• Menstrual cycle normalization in 80% of responsive patients 3
• Enhanced natural pregnancy rates when combined with metformin 2

Sertraline does not typically cause the constellation of symptoms described but should be reviewed for contribution to fatigue.

Diagnostic Algorithm Priority

1. Morning (8 AM) hormonal panel: TSH, free T4, cortisol, ACTH, FSH, LH, estradiol, electrolytes 1
2. Metabolic assessment: Fasting glucose, HbA1c, lipid panel, CRP 2
3. EBV evaluation: EBV serology (VCA-IgG, EA-IgG), quantitative EBV PCR 5
4. Lymphoproliferative screening: CBC with differential, LDH, β2-microglobulin, ESR 5
5. If cortisol 3-15 μg/dL: ACTH stimulation test 1
6. If multiple pituitary deficiencies: MRI brain with pituitary cuts 1