In a 20‑year‑old trans‑male receiving weekly intramuscular testosterone (≈0.3 mL) with a serum testosterone of 45 ng/dL who now has dysmenorrhea and abnormal uterine bleeding, what is the most likely cause and how should it be managed?

Inadequate Testosterone Dosing Causing Breakthrough Bleeding in a Trans‑Male Patient

This patient's testosterone level of 45 ng/dL is profoundly subtherapeutic—well below the target range of 450–600 ng/dL—and is the direct cause of his dysmenorrhea and abnormal uterine bleeding. 1 The current weekly dose of 0.3 mL testosterone (likely ≈60 mg if using 200 mg/mL concentration) is insufficient to suppress endometrial activity and maintain amenorrhea. 1, 2

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Understanding the Problem

Why Breakthrough Bleeding Occurs

• Inadequate androgen suppression permits persistent endometrial activity; even with amenorrhea, 69 % of trans‑masculine persons on testosterone retain proliferative or secretory endometrium on histopathology. 3
• A testosterone level of 45 ng/dL is far below the physiologic male range (300–1,000 ng/dL) and fails to suppress hypothalamic‑pituitary‑ovarian signaling, allowing estradiol production to continue unopposed. 1
• Unopposed estrogen stimulation drives endometrial proliferation, which eventually outgrows its blood supply and sheds irregularly, manifesting as abnormal uterine bleeding and dysmenorrhea. 4, 5

Endometrial Histology on Testosterone

• Despite regular testosterone therapy, 61.8 % of trans men show atrophic endometrium, 17.6 % proliferative, and 20.6 % secretory patterns; however, this distribution assumes therapeutic testosterone levels. 6
• With subtherapeutic dosing (as in this case), the endometrium remains hormonally active and vulnerable to breakthrough bleeding. 3

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Immediate Diagnostic Steps

Confirm the Testosterone Formulation and Actual Dose

• Verify the concentration of the testosterone preparation (typically 200 mg/mL for cypionate or enanthate); if 0.3 mL of a 200 mg/mL vial is being used, the weekly dose is only 60 mg, which is at the lower end of the recommended range (50–100 mg weekly). 2
• Measure a repeat fasting morning total testosterone (8–10 AM) to confirm persistent subtherapeutic levels; a single value of 45 ng/dL is diagnostic, but repeat testing ensures accuracy. 1

Rule Out Structural or Pathologic Causes

• Obtain a transvaginal ultrasound to assess endometrial thickness and exclude polyps, fibroids, or other structural lesions that can cause abnormal bleeding independent of hormone status. 4
• Perform an endometrial biopsy if the patient is ≥35 years, has risk factors for endometrial hyperplasia (obesity, prolonged anovulation), or if bleeding persists despite dose optimization; this excludes hyperplasia or malignancy. 4, 7
• In this 20‑year‑old with recent‑onset symptoms and clear subtherapeutic testosterone, biopsy can be deferred if bleeding resolves after dose escalation. 3

Assess for Coexisting Causes

• Check hemoglobin/hematocrit to quantify blood loss and rule out anemia. 4
• Obtain a sensitive urine or serum β‑hCG to exclude pregnancy (even in trans men, ovulation can occur with subtherapeutic testosterone). 4
• Measure thyroid‑stimulating hormone (TSH) because thyroid dysfunction can independently cause menstrual irregularities. 8

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Treatment Algorithm

Step 1: Escalate Testosterone Dose Immediately

• Increase the weekly intramuscular dose to 100 mg (0.5 mL of 200 mg/mL testosterone cypionate or enanthate) to achieve target serum testosterone of 450–600 ng/dL. 1, 2
• Recheck testosterone levels 2–3 months after dose adjustment, drawn midway between injections (days 3–4 for weekly dosing), targeting mid‑normal values. 1, 2
• If levels remain subtherapeutic at 100 mg weekly, escalate to 150 mg weekly or consider switching to a transdermal gel (40.5 mg daily of 1.62 % gel) for more stable serum concentrations. 1, 2

Step 2: Provide Acute Symptomatic Relief

• For dysmenorrhea, prescribe a nonsteroidal anti‑inflammatory drug (NSAID) such as ibuprofen 400–600 mg every 6 hours as needed or naproxen 500 mg twice daily; NSAIDs inhibit prostaglandin synthesis and reduce menstrual pain. 5
• For heavy or prolonged bleeding, consider a short course of medroxyprogesterone acetate 10 mg daily for 10–14 days to stabilize the endometrium and induce a withdrawal bleed, followed by resumption of optimized testosterone therapy. 7, 4
• Alternatively, combined oral contraceptives (30–35 mcg ethinyl estradiol) for 21 days can rapidly suppress bleeding through endometrial atrophy; this is appropriate if the patient can tolerate estrogen and does not object to its use. 4, 5

Step 3: Monitor Response

• Reassess at 4–6 weeks after dose escalation to evaluate resolution of bleeding and dysmenorrhea. 1
• Repeat testosterone level at 2–3 months to confirm therapeutic range (450–600 ng/dL). 1, 2
• If bleeding persists despite achieving target testosterone levels, proceed to transvaginal ultrasound and endometrial biopsy to exclude structural pathology or hyperplasia. 4

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Expected Outcomes

With Dose Optimization

• Amenorrhea is achieved in the majority of trans men once serum testosterone reaches the physiologic male range (≥300 ng/dL, ideally 450–600 ng/dL). 1, 6
• Endometrial atrophy develops over 3–6 months of therapeutic testosterone exposure, eliminating the substrate for breakthrough bleeding. 6
• Dysmenorrhea resolves as menstrual cycles cease and prostaglandin‑mediated uterine contractions are suppressed. 5

If Bleeding Persists

• Persistent bleeding despite therapeutic testosterone (>600 ng/dL for ≥3 months) warrants endometrial biopsy to exclude hyperplasia or malignancy, as prolonged unopposed estrogen (from subtherapeutic dosing) may have induced pathologic changes. 3, 4
• One case of complex hyperplasia without atypia has been reported in a cohort of 94 trans men on testosterone, underscoring the need for histologic evaluation when bleeding does not resolve. 3

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Critical Pitfalls to Avoid

• Do not continue the current subtherapeutic dose (0.3 mL weekly ≈ 60 mg); this perpetuates endometrial activity and bleeding. 1, 2
• Do not attribute bleeding to "normal adjustment" when testosterone levels are profoundly low (45 ng/dL); this is a dosing failure, not a physiologic transition. 1
• Do not delay dose escalation while pursuing extensive workup; the most likely cause is inadequate testosterone, and empiric dose increase is both diagnostic and therapeutic. 1, 2
• Do not omit pregnancy testing even in trans men on testosterone, as ovulation can occur with subtherapeutic levels. 4
• Do not prescribe progestin‑only contraceptives (e.g., depot medroxyprogesterone) as long‑term management without first optimizing testosterone; the goal is to achieve amenorrhea through adequate androgen therapy, not to add another hormone. 7, 4

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Long‑Term Considerations

Monitoring Protocol

• Testosterone levels every 6–12 months once stable, drawn midway between injections, targeting 450–600 ng/dL. 1, 2
• Hemoglobin/hematocrit annually to surveil for erythrocytosis (risk ≈15 % with transdermal, 44 % with injectable testosterone). 1
• No routine endometrial surveillance is required in asymptomatic trans men with amenorrhea on therapeutic testosterone; biopsy is reserved for persistent or recurrent bleeding. 3

Formulation Considerations

• Injectable testosterone (cypionate/enanthate 100–150 mg weekly) is cost‑effective ($156/year) and achieves reliable serum levels when dosed appropriately. 2
• Transdermal gel (1.62 % at 40.5 mg daily) provides more stable day‑to‑day testosterone concentrations and a lower erythrocytosis risk (15 % vs. 44 %), but costs significantly more ($2,135/year). 1, 2
• Weekly dosing (50–150 mg) is superior to biweekly dosing (100–200 mg every 2 weeks) because it minimizes peak‑trough fluctuations and reduces erythrocytosis risk. 2

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Summary of Recommended Actions

1. Increase testosterone cypionate or enanthate to 100 mg (0.5 mL of 200 mg/mL) intramuscularly weekly. 1, 2
2. Prescribe ibuprofen 400–600 mg every 6 hours as needed for dysmenorrhea. 5
3. Consider a 10–14‑day course of medroxyprogesterone acetate 10 mg daily to acutely stabilize heavy bleeding, then resume optimized testosterone. 7, 4
4. Recheck testosterone level at 2–3 months (drawn midway between injections), targeting 450–600 ng/dL. 1, 2
5. Obtain transvaginal ultrasound and endometrial biopsy only if bleeding persists after 3 months of therapeutic testosterone levels. 3, 4