Abstract While endocrinologists continue to initiate gender-affirming hormone therapy (GAHT) in healthy transgender and gender diverse (TGD) patients, they may also encounter more TGD patients in their clinics with complex medical histories that influence the patient-provider shared decision-making process for initiating or continuing GAHT. The purpose of this Approach to the Patient article is to describe management considerations in 2 adults with thromboembolic disease and 2 adults with low bone mineral density in the setting of feminizing and masculinizing GAHT.
Sam: Stopping hormones after a medical crisis is not automatically the safest long-term choice. This clinical guide argues for weighing the benefits and risks of continuing treatment against those of withholding it.
Alex: That sounds consequential for patients whose treatment gets interrupted after a serious illness. What kind of guidance are we talking about?
Sam: It’s a case-based clinical guide from Sean Iwamoto and colleagues, published in the Journal of Clinical Endocrinology and Metabolism. They examine gender-affirming hormone therapy: hormone treatment supporting a person’s gender affirmation. Their focus is adults with blood clots, stroke, or low bone density.
Alex: So this is for the difficult decisions that broad prescribing recommendations don’t completely resolve.
Sam: Yes, especially for clinicians treating people with overlapping medical risks. We’ll follow how the authors adapt treatment, what evidence supports those choices, and where clinical judgment outruns the data.
Alex: Before the cases, what does this add to existing guidance? Are the authors challenging an established approach?
Sam: They’re applying it, rather than replacing it. Published guidelines already describe safe prescribing and expected outcomes. This article uses four clinical cases to work through what happens when serious illness complicates starting or continuing hormones. Its contribution is the reasoning, not a newly tested treatment strategy.
Alex: Let’s start with the clotting question. What makes estrogen treatment difficult to manage after a clot?
Sam: The first patient is a transgender woman who developed a pulmonary embolism, a blood clot in the lungs. She was taking injectable estrogen and progesterone. The emergency team started medication to prevent further clotting and told her to stop estrogen pending specialist review.
Alex: The event happened during treatment, but that alone doesn’t establish what caused it. What does the wider evidence show?
Sam: In the American STRONG study, researchers followed about twenty-eight hundred transgender women. Their adjusted clotting risk was roughly twice that of cisgender comparison groups, both men and women. But the absolute rate remained low: about three events per thousand person-years.
Alex: So the relative increase matters, but it shouldn’t make a rare event sound common. Can those averages tell us which estrogen preparation is safest?
Sam: Not reliably. The large retrospective studies couldn’t account for estrogen route, dose, or type. They also didn’t account for preexisting illnesses or their risk factors. That’s the central limitation when translating these population findings into a decision for someone who has already had a clot.
Alex: Yet the authors still prefer some routes over others. What supports that distinction?
Sam: Oral estrogen shifts the production of clotting factors toward a more clot-prone state more than estrogen delivered through the skin. That skin route is called transdermal treatment. Drawing on mechanistic and clinical evidence, the authors describe it as preferred for people at higher clotting risk and for older adults.
Alex: A preferred route only helps if the patient can actually use it. Did that work for this woman?
Sam: She had already struggled with patches, including poor absorption and skin irritation. She strongly wanted to continue hormones. After discussing risks, the clinicians continued low-dose weekly injections alongside anticoagulation, medication that prevents clotting. The reasoning included avoiding the liver’s first processing of oral estrogen.
Alex: That sounds individualized, but it isn’t evidence that injections are equally safe after a clot.
Sam: It isn’t. This is a clinical choice, not a comparative safety result. The authors emphasize avoiding hormone levels above the physiological range and involving hematology specialists. They also note that guidelines don’t provide a specific estrogen target for high-risk patients.
Alex: What about the progesterone she was also taking? Does the article separate its potential contribution?
Sam: It discusses an observational association with clotting, but the event count was small and the uncertainty wide. That cannot establish causation. The authors also note that guidelines don’t recommend routine progesterone use in feminizing treatment because evidence of benefit is lacking.
Alex: Let’s turn to testosterone. Does the same clotting concern apply to masculinizing treatment?
Sam: The evidence differs. In the STRONG cohort, about twenty-one hundred transgender men did not have significantly higher clot or ischemic stroke risk than cisgender comparison groups. An ischemic stroke happens when blood flow to part of the brain is blocked. The reviewed evidence also did not show testosterone making clotting factors more pro-clotting in transgender men.
Alex: But a reassuring population comparison doesn’t settle whether someone should restart testosterone after a stroke. How did the authors handle that?
Sam: Their patient had several cardiovascular risk factors and had stopped testosterone after his stroke. Off treatment, he developed fatigue, generalized pain, and reduced facial hair. He wanted to restart while working with neurology on stroke prevention, including medication adherence and behavioral changes.
Alex: So the choice wasn’t between hormones and prevention. They addressed both together.
Sam: They restarted with testosterone gel rather than injections. Testosterone can raise hematocrit, the proportion of blood occupied by red blood cells. But the authors explicitly say studies are lacking on whether switching high-risk patients from injections to skin treatment improves outcomes. That distinction between reasonable judgment and demonstrated benefit is essential.
Alex: The bone cases introduce a different concern: withholding hormones can itself become a physical risk. When does that matter most?
Sam: Particularly after gonadectomy, surgical removal of the ovaries or testes. The next patient had stopped estrogen after removal of her testes and later presented with hot flashes and joint pain. A bone-density scan showed very low density at the spine. She had no reported fracture history.
Alex: Does low density in someone who used hormones imply the hormones damaged bone?
Sam: No. The article describes low bone density in some transgender women even before treatment. Long-term hormone treatment is generally associated with at least maintaining bone density. Here, the prolonged period without adequate sex hormones after surgery was a reason to investigate bone loss.
Alex: How did the clinicians turn that into a treatment plan without ignoring why she had stopped?
Sam: They acknowledged that she had met her gender affirmation goals and discussed her concerns about weight and emotional changes. She restarted oral estrogen because skin treatment wasn’t well tolerated, alongside calcium, vitamin D, and general bone-health measures. At follow-up, she reported feeling well and her joint pains had disappeared. A repeat scan was planned; the case doesn’t establish bone recovery.
Alex: And the final case asks whether testosterone is a problem when bone disease is already complicated by other illnesses.
Sam: A transgender man had low bone density alongside severe kidney disease, an eating disorder, and a history of heavy alcohol use. His bone density initially improved after starting hormones, while he also gained weight and changed his habits. Later losses could have reflected kidney-related hormonal problems and ongoing alcohol consumption.
Alex: So attributing the bone changes to testosterone alone would miss several competing explanations.
Sam: The authors’ broader conclusion is that low bone-density scores are not themselves a contraindication to starting hormones. Care also needs fracture-risk assessment, attention to other causes, and mental health support. They recommend bone-density screening when risk factors exist, rather than routine scanning for every transgender person.
Alex: Who should read the full article, and where would you send them first?
Sam: Clinicians managing gender-affirming hormones in medically complex adults should read the case-specific management discussions. Start with the pulmonary embolism case for route selection and anticoagulation, or the bone-health cases for screening and treatment continuity. Researchers studying hormone safety should examine where the authors explicitly identify missing comparisons. This is a useful guide to decisions, not proof that the chosen regimens are safest.
Alex: And what should everyone else carry away?
Sam: Stopping treatment is also a treatment decision, with benefits and risks of its own.
Alex: Thanks for listening.