Long-term oncological implications of hormone-replacement therapy in women with Kallmann syndrome: A propensity-matched study from the Global Federated Health Research Network.

e22525 Background: Kallmann syndrome is a rare genetic condition known for its characteristic hypogonadotropic hypogonadism and anosmia. Kallmann syndrome is most often seen in males, but a smaller subset of females is diagnosed with the condition. Females with Kallmann syndrome can be treated with hormone-replacement therapy (HRT) that includes estrogen and progestin. Unfortunately, estrogen use has been associated with higher rates of multiple cancers. Despite the prevalence of HRT in the United States, there is little information regarding oncological outcomes among women on HRT with Kallmann syndrome. Methods: We utilized TriNetX’s US Collaborative Network to investigate rates of development of estrogen-associated cancers in female patients diagnosed with Kallmann syndrome using ICD-10 codes. We identified female patients diagnosed with Kallmann syndrome aged over 18 years and stratified those as having taken and not taken HRT. Kallmann patients with HRT were matched with a control group of Kallmann patients without HRT based on age, race, and comorbidities. We followed these patients to assess rates of breast, cervical, uterine, ovarian, and colorectal cancer development as well as development of deep venous thromboses, pulmonary emboli, and depression. Results: Following propensity score matching, we identified 14,895 female patients in each cohort all with diagnosed Kallmann syndrome, with and without documented use of HRT. The average age at index for Kallmann syndrome patients without HRT was 44.7 +/- 20.3 years old, compared to Kallmann syndrome patients with HRT, which was 49.4 +/- 19.4 years old. Within the Kallmann syndrome and HRT cohort, the ethnic distribution was predominantly Caucasian (57.1%), followed by Black (15.6%), Hispanic (9.7%), and Asian (5.5%). In the Kallmann syndrome without HRT cohort, the ethnic distribution was also predominantly Caucasian (63.8%), followed by Black (16.3%), Hispanic (10.3%), and Asian (4.3%). The Kallmann syndrome without HRT group had a significantly higher risk of developing breast cancer (HR 0.409, 95% CI 0.367 - 0.456, p < 0.001), deep venous thrombosis (HR 0.948, 95% CI 0.828 - 1.085, p = 0.036), and depression (HR 0.926, 95% CI 0.889 - 0.965, p = 0.016). Conclusions: Our findings indicate that female patients with Kallmann syndrome not taking HRT have a significantly higher risk of developing breast cancer and deep venous thromboses as compared with female patients with Kallmann syndrome taking HRT. Cohorts did not demonstrate a statistically significant difference in rates of uterine, ovarian, cervical, colorectal cancer, or pulmonary embolism. Understanding these outcomes could lead to a better understanding of hormonal interactions in a population that is poorly understood. Further studies are warranted to more thoroughly understand this patient population.