Long-Term Oncological Implications of Hormone Replacement Therapy in Women With Hypogonadotropic Hypogonadism: A Propensity-Matched Study.

Introduction Hypogonadotropic hypogonadism (HH), or secondary gonadal dysfunction, is a result of gonadal failure due to deficiencies in gonadotropin secretion, caused by hypothalamic or anterior pituitary dysfunction. There are multiple forms of HH, with the syndrome divided into congenital, acquired organic, and functional forms. The relationship between HH and oncological processes is complex and multidirectional, and little is known about the relationship between HH and cancer in female patients. Hormone replacement therapy (HRT) can be important for symptom control in many women with HH. However, exogenous estrogen use is additionally associated with a higher risk of both arterial and venous thromboses. There is little information available regarding the impact of HRT on rates of cancers or thromboses in women with HH. Methods TriNetX's US Collaborative Network was utilized to study rates of development of estrogen-associated cancers in female patients at or above 50 years old diagnosed with HH using ICD-10 codes. Adult female patients diagnosed with HH were identified and stratified according to HRT use and ICD-10 codes. HH patients prescribed HRT were matched with a control group of HH patients without HRT based on age, ethnicity, race, and comorbidities. Patients were followed to assess rates of estrogen-associated cancer development at any time after the index event, defined as HH development with or without HRT prescription, or menopause development. Cancers studied included breast, cervical, uterine, ovarian, endometrial, gastric, and colorectal cancer. Development of venous thromboses, including deep venous thromboses (DVTs) and pulmonary emboli (PEs), was also studied. Patients with outcomes prior to the indexing date were excluded from the study.  Results Following propensity-score matching, we identified 8,293 female patients at or above 50 years old in each cohort, with diagnosed HH, but with and without prescribed HRT. There were no significant differences in rates of breast, cervical, uterine, ovarian, endometrial, or colorectal cancers between HH cohorts. There were no significant differences in rates of DVTs or PEs between HH cohorts. A cohort of female patients at or above 50 years old with HH and no HRT prescription was propensity-score matched with a cohort of post-menopausal women at or above 50 years old without HH or HRT prescription. There were no significant differences in rates of breast, colorectal, cervical, or ovarian cancers. The postmenopausal cohort demonstrated a significantly increased risk of endometrial cancer (HR 0.246, 95% CI 0.220 - 0.275, p<0.001). The HH without HRT cohort demonstrated a significantly increased risk of gastric cancer (HR 3.150, 95% CI 2.549 - 3.892, p=0.001), acute DVT (HR 1.709, 95% CI 1.595 - 1.831, p<0.001), and acute PE (HR 1.612, 95% CI 1.494 - 1.740, p<0.001).  Conclusions Our findings indicate that female patients at or above 50 years old with HH may have an elevated risk of venous thromboses and gastric cancer, but reduced risk of endometrial cancer when compared to a cohort of post-menopausal female patients above 50 years old without HRT prescription. No significant differences existed between cohorts with HH with and without HRT prescription. Further study into this population is warranted.