Danish researchers have found that oral oestrogen therapy is associated with significantly higher odds of porphyria cutanea tarda, while non-oral formulations show no statistically significant association.
Women using oestrogen-containing therapies have more than twice the odds of developing porphyria cutanea tarda, with oral formulations appearing to carry the greatest risk, according to new research.
The nationwide Danish study, published in JAMA Dermatology, found that oestrogen-containing therapy was associated with a twofold increase in the odds of developing the rare photosensitive skin disorder, even after adjusting for established risk factors.
However, the association varied considerably according to the route of administration, with oral oestrogen-only therapy associated with significantly higher odds of PCT, while vaginal and other non-oral formulations were not.
The researchers said the findings provided some of the strongest population-based evidence to date linking estrogen exposure to PCT and could help clinicians make more informed decisions about hormone therapy in susceptible patients.
“At a population level, the risk of PCT associated with oestrogen-containing hormonal therapies is negligible,” they wrote.
“However, in patients with PCT, this study supports current recommendations to avoid oestrogen when possible and adds that oral oestrogen-containing therapy may be more clinically relevant than nonoral routes.”
Researchers from Copenhagen University Hospital and the University of Copenhagen analysed nationwide registry data collected between January 1995 and November 2024.
They identified 438 women with a first-time hospital diagnosis of PCT and matched each with 100 population controls, producing a comparison group of 43,800 women. The median age of women with PCT was 61 years.
Among women diagnosed with PCT, 35.2% had received oestrogen-containing therapy in the preceding year, compared with 21.5% of controls.
After adjustment for HIV infection, liver disease, viral hepatitis, iron overload, smoking-related conditions, and alcohol or drug misuse, oestrogen exposure was associated with approximately double the odds of PCT (adjusted odds ratio 2.03; 95% confidence interval 1.66-2.49).
The association was evident across different types of hormonal treatment.
Oestrogen-containing contraceptives were associated with a 2.52-fold increase in the odds of PCT (95% CI 1.67-3.82), while combined oestrogen-progestogen therapy was associated with a 2.18-fold increase (95% CI 1.53-3.11).
Oestrogen-only therapy was associated with a smaller but statistically significant increase (adjusted OR 1.58; 95% CI 1.23-2.03).
The researchers also found substantial differences when they examined estrogen-only therapy according to its route of administration.
Oral oestrogen was associated with a 2.44-fold increase in the odds of PCT (95% CI 1.66-3.59), while vaginal estrogen showed no statistically significant association (adjusted OR 1.19; 95% CI 0.87-1.63).
Other non-oral formulations, including transdermal and parenteral oestrogen, were also not significantly associated with PCT (adjusted OR 1.65; 95% CI 0.77-3.54).
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A direct comparison found that oral oestrogen was associated with approximately twice the odds of PCT compared with vaginal oestrogen (adjusted OR 2.05; 95% CI 1.25-3.38).
The researchers suggested that the difference could be explained by the first-pass metabolism of oral oestrogen in the liver, which results in greater hepatic exposure than nonoral administration.
This may be particularly relevant to PCT, which develops when reduced activity of the hepatic enzyme uroporphyrinogen decarboxylase leads to the accumulation of photosensitising porphyrins in the skin and liver.
The disorder typically presents with skin fragility, blistering, and erosions on sun-exposed areas, particularly the backs of the hands, forearms, and face.
Although oestrogen exposure has long been recognised as a potential precipitating factor, previous evidence has largely come from case reports and small clinical series rather than population-based comparative studies.
The researchers said their findings supported oestrogen-containing therapy as a risk factor in both premenopausal and postmenopausal treatment settings.
They also suggested that the route-specific findings could help refine counselling for women with PCT who require hormone therapy.
At a population level, however, the absolute risk associated with oestrogen-containing therapies remains negligible because PCT is rare.
The researchers noted that the observational design could not establish causation. Prescription records also could not confirm whether women had taken the medications, while incomplete information about smoking and alcohol consumption meant residual confounding remained possible.
The study included only women with hospital-diagnosed PCT, potentially excluding milder cases managed outside hospital settings. The small number of women using some non-oral formulations also limited the precision of those estimates.
Nevertheless, the researchers said the findings reinforced existing recommendations to avoid estrogen where possible in patients with PCT, while suggesting oral oestrogen may warrant particular consideration.
“In this case-control study, we found evidence supporting oestrogen-containing therapy as a clinically relevant risk factor for incident PCT,” they concluded.
“In route-specific analyses, the association was observed only for oral oestrogen-containing therapy, whereas nonoral estrogen-containing therapy routes were not associated with PCT.
“These findings refine the clinical interpretation of hormone-associated PCT and may support more nuanced counselling for female individuals with PCT who require oestrogen-containing therapy.”
