Menopausal Hormone Therapy Linked to Increased Risk of Pituitary Adenoma

Woman sitting down holding a pack of menopausal hormone therapy pills

Although pituitary adenomas are relatively common, few risk factors have been identified. However, convincing evidence has been published that estrogen stimulates lactotroph cells in the pituitary gland.

Meir J. Stampfer, MD, DrPH, of the Channing Division of Network Medicine at Brigham and Women’s Hospital, David J. Cote, MD, PhD, formerly an MD/PhD student at the T.H. Chan School of Public Health and now a neurosurgery resident at the University of Southern California, and colleagues have conducted the first prospective study of associations between the use of oral contraceptives (OCs) or menopausal hormone therapy (MHT) and risk of pituitary adenoma.

In The Journal of Clinical Endocrinology & Metabolism, they report a strong positive association between the use of MHT and the incidence of pituitary adenoma, with more than doubled risk for more than five years of use compared with never-users. There was no substantial association between OC use and pituitary adenoma.

Methods

The researchers conducted two complementary analyses in parallel. The prospective analysis examined data from two very large longitudinal epidemiologic studies, the Nurses’ Health Study (started in 1976 with an enrollment of 121,701 female registered nurses ages 30–55) and the Nurses’ Health Study II (started in 1989 with an enrollment of 116,686 female registered nurses ages 25–42).

Separately, from the Mass General Brigham Research Patient Data Registry, the researchers identified 5,469 women with pituitary adenoma diagnosed between 2010 and 2020. They matched those patients to 6,262 control subjects on age, race, sex, and healthcare use.

Nurses’ Health Studies

Over 6,668,019 person-years of follow-up, 331 participants in the prospective studies reported a new diagnosis of pituitary adenoma. In pooled analyses, there were no strong associations between OC use and a higher risk of pituitary adenoma:

  • Past use vs. never use—adjusted HR (aHR), 1.05; 95% CI, 0.80–1.36
  • Current use vs. never use—aHR, 0.72; 95% CI, 0.40–1.32
  • >5 years of use vs. never use—aHR, 0.95; 95% CI, 0.68–1.31 (P for trend = 0.43)

In contrast, strong positive associations were noted between MHT use and the incidence of pituitary adenoma:

  • Past use vs. never use—aHR, 2.00; 95% CI, 1.50–2.68
  • Current use vs. never use—aHR, 1.80; 95% CI, 1.27–2.55
  • >5 years of use vs. never use—aHR, 2.06; 95% CI, 1.42–2.99 (P for trend = 0.002)

Positive associations with MHT were observed for both estrogen-only and estrogen plus progestin formulations.

When OC and MHT use were cross-classified, strong positive associations were identified between MHT use and pituitary adenoma with or without OCs. No such associations were identified for OC use in the absence of MHT use.

Registry Analysis

The case–control analysis confirmed an increased risk of pituitary adenoma among users of MHT and also demonstrated mildly increased risk in individuals who had ever used OCs:

  • Ever use of MHT vs. never use—adjusted OR (aOR), 1.57; 95% CI, 1.35–1.83
  • Ever use of OCs vs. never use—aOR, 1.27; 95% CI, 1.14–1.42

The strong association between MHT use and incidence of pituitary adenoma, with evidence of a duration effect, may have value for risk stratification and mechanistic insight into tumorigenesis.

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