In a transgender male with retained ovaries receiving five 75‑mg subcutaneous testosterone pellets (last insertion on [date]), with a serum testosterone peak of approximately 716 ng/dL and trough of approximately 294 ng/dL (drawn a few days after the 4‑week and 12‑week marks) and estradiol in the cis‑male range, why is free testosterone persistently low and the testosterone‑to‑SHBG ratio reduced despite low‑normal total testosterone, and what management steps are recommended?

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Last updated: September 30, 2026 • View editorial policy

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Elevated SHBG with Low Free Testosterone in Early Testosterone Therapy

The persistently low free testosterone and elevated SHBG despite adequate total testosterone levels is a well-recognized, transient phenomenon during the first 3–9 months of testosterone therapy in transgender men, particularly in those with retained ovaries, and does not require immediate dose escalation. 1

Understanding the Physiology

The Endocrine Society guidelines explicitly address this exact scenario: "During the first 3–9 months of testosterone treatment, total testosterone levels may be high, although free testosterone levels are normal, due to high SHBG levels in some biological women." 1 This is a predictable physiological response in individuals assigned female at birth who are initiating testosterone therapy.

Why This Happens

  • Residual ovarian activity: With ovaries still present and estradiol in the cis-male range (which is appropriate), there remains some estrogenic influence that can maintain elevated SHBG production
  • SHBG lag period: The liver's production of SHBG takes several months to downregulate in response to sustained testosterone exposure
  • Recent evidence confirms: A 2025 study demonstrated that testosterone therapy in transmasculine persons decreases SHBG by 43% over 12 months, but this decline is gradual 2

Interpreting Your Patient's Levels

Your patient's testosterone levels warrant careful interpretation:

  • Peak of 716 ng/dL: Within normal male range (320–1000 ng/dL per guidelines) 1
  • Trough of 294 ng/dL: Just below the 300 ng/dL threshold, but the timing is critical here
  • Timing caveat: Both measurements were drawn "a few days past" their intended timepoints (4 and 12 weeks), meaning the true trough is likely higher than 294 ng/dL

The Trough Below 400: Context Matters

While you note the trough is below 400 ng/dL, the guideline targets are actually more nuanced. The Endocrine Society specifies maintaining testosterone "in the normal physiological male range" of 320–1000 ng/dL, with specific monitoring recommendations based on formulation. 1 For pellet therapy specifically, research shows that testosterone levels naturally decline over the implantation period, with reimplantation typically needed at 100–120 days 3.

Management Algorithm

1. Do Not Increase Dose Yet

Given that your patient is likely still within the first year of therapy (based on the context), the appropriate action is watchful waiting with continued monitoring, not dose escalation. The low free testosterone with elevated SHBG should normalize as therapy continues beyond 9 months.

2. Optimize Timing of Laboratory Draws

For subcutaneous testosterone pellets:

  • Peak levels: Should be measured 1–2 weeks post-insertion 3, 4
  • Trough levels: Should be measured at 12–16 weeks (just before next insertion is due) 3
  • Your patient's labs drawn "a few days past" the intended timepoints may underestimate the true trough

3. Reassess at 9–12 Months

If free testosterone remains low and SHBG remains elevated beyond 9 months of therapy, then consider:

  • Increasing pellet number from 5 pellets (375 mg) to 6–8 pellets (450–600 mg)
  • Research in cisgender hypogonadal men shows 6–9 pellets provide adequate levels with lower estradiol peaks than 10–12 pellets 3
  • For transgender men specifically, case reports suggest similar dosing to cisgender men (450–900 mg) 5

4. Monitor for Adequate Virilization

Rather than focusing solely on laboratory values, assess clinical endpoints of adequate testosterone therapy: 1

  • Cessation of menses (if not yet achieved)
  • Progressive voice deepening
  • Facial and body hair growth
  • Redistribution of body fat and muscle mass
  • Improvement in gender dysphoria

If virilization is progressing appropriately despite the laboratory findings, this further supports that the current dose is adequate.

The Ovarian Factor

The presence of retained ovaries complicates the hormonal milieu but does not necessarily require intervention if estradiol is controlled. Your patient's estradiol is appropriately in the cis-male range, which is the target. 1 The guidelines recommend monitoring estradiol during the first 6 months or until menses cease, with a target of <50 pg/mL.

Consider Oophorectomy Discussion

While not immediately necessary, patients with retained ovaries may benefit from bilateral oophorectomy for several reasons:

  • Eliminates endogenous estrogen production
  • May improve SHBG normalization
  • Reduces long-term testosterone dose requirements
  • Eliminates need for ongoing estradiol monitoring

Common Pitfalls to Avoid

  1. Premature dose escalation: Increasing testosterone dose in the first 9 months based on low free testosterone alone can lead to supraphysiological total testosterone levels and increased adverse effects (erythrocytosis, hepatotoxicity, cardiovascular risk) 1

  2. Ignoring timing of pellet kinetics: Pellet therapy has unique pharmacokinetics with peak levels in the first 2 weeks and steady decline thereafter. A trough of 294 ng/dL at >12 weeks may be acceptable if the patient is due for reimplantation 3, 4

  3. Over-reliance on free testosterone in early therapy: The guidelines specifically warn that free testosterone may appear low relative to total testosterone in the first 3–9 months due to elevated SHBG—this is expected and transient 1

Pellet Reimplantation Timing

Based on pharmacokinetic data, testosterone pellets should be reimplanted every 100–120 days (approximately 3.5–4 months). 3 If your patient's trough was drawn at 12+ weeks, they are approaching the time for next insertion, which will restore levels to the therapeutic range.

Dosing Considerations for Next Insertion

  • Current dose: 5 pellets (375 mg)
  • If trough remains <300 ng/dL at appropriate timing, consider 6–7 pellets (450–525 mg)
  • Avoid jumping to 10–12 pellets, as this significantly increases estradiol through aromatization 3

Bottom Line

Your patient's laboratory findings represent the expected physiological response to testosterone therapy in the first year, particularly with retained ovaries. The combination of low-normal total testosterone, low free testosterone, and elevated SHBG will likely resolve spontaneously as therapy continues beyond 9 months. Continue current dosing, ensure proper timing of laboratory monitoring, and reassess both clinical virilization and laboratory parameters at 9–12 months before considering dose adjustment. The trough of 294 ng/dL, while below your preferred 400 ng/dL, is acceptable given the timing of the draw and the transient nature of the SHBG elevation.

References

1
Guideline

endocrine treatment of transsexual persons: an endocrine society clinical practice guideline.

The Journal of clinical endocrinology and metabolism, 2009

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