Changes to hypothalamic volume and associated subunits during gender-affirming hormone therapy

Abstract

Background: Among its pleiotropic properties, gender-affirming hormone therapy (GHT) affects regional brain volumes. The hypothalamus, which regulates neuroendocrine function and associated emotional and cognitive processes, is an intuitive target for probing GHT effects. We sought to assess changes to hypothalamus and hypothalamic subunit volumes after GHT, thereby honouring the region's anatomical and functional heterogeneity.

Methods: Individuals with gender dysphoria and cisgender controls underwent 2 MRI measurements, with a median interval of 145 days (interquartile range [IQR] 128.25-169.75 d, mean 164.94 d) between the first and second MRI. Transgender women (TW) and transgender men (TM) underwent the first MRI before GHT and the second MRI after approximately 4.5 months of GHT, which comprised estrogen and anti-androgen therapy in TW or testosterone therapy in TM. Hypothalamic volumes were segmented using FreeSurfer, and effects of GHT were tested using repeated-measures analysis of covariance.

Results: The final sample included 106 participants: 38 TM, 15 TW, 32 cisgender women (CW) and 21 cisgender men (CM). Our analyses revealed group × time interaction effects for total, left and right hypothalamus volume, and for several subunits (left and right inferior tubular, left superior tubular, right anterior inferior, right anterior superior, all p _corr < 0.01). In TW, volumes decreased between the first and second MRI in these regions (all p _corr ≤ 0.01), and the change from the first to second MRI in TW differed significantly from that in CM and CW in several subunits (p _corr < 0.05).

Limitations: We did not address the influence of transition-related psychological and behavioural changes.

Conclusion: Our results suggest a subunit-specific effect of GHT on hypothalamus volumes in TW. This finding is in accordance with previous reports of positive and negative effects of androgens and estrogens, respectively, on cerebral volumes.

Figure 1

Decreased volumes of the hypothalamus and associated subunits in transgender women (TW) after gender-affirming hormone therapy (GHT). Post hoc comparisons between baseline MRI (MRI 1) and after approximately 4.5 months (MRI 2) of GHT in TW and transgender men (TM; no therapy in cisgender men [CM] and cisgender women [CW]) show significant volumetric reduction, in cubic millimetres, in the whole hypothalamus; in the left and right hypothalamus separately; and in the left and right inferior tubular subunit, right anterior inferior subunit, right anterior superior subunit, left superior tubular subunit in TW. *p_corr ≤ 0.01.