Estrogen exposure and skeletal health: Special populations and considerations

Abstract

Estrogen is critical for bone health from puberty onwards. Various clinical scenarios in adolescence can impact skeletal exposure to estrogen during this vulnerable time. Primary ovarian insufficiency, premature menopause, and anorexia nervosa necessitate prompt evaluation, treatment, and replacement of estrogen in order to optimize accrual of peak bone mass. We have much still to learn about the skeletal impact of delaying puberty and gender affirming hormones in gender diverse individuals. While the choice of hormonal contraception in adolescence is often driven by patient preference and concerns about adherence, providers and patients much take the long-term impact on bone health into consideration.

Key concepts: (1)Delayed, diminished or absent estrogen during adolescence has a negative impact on peak bone mass accrual.(2)Hormone replacement therapy is essential for patients with primary ovarian insufficiency and premature menopause.(3)Recovery from anorexia nervosa does not lead to a complete catch-up of bone density lost/not gained.(4)Not all hormonal contraception methods are created equal for the adolescent skeleton.(5)Skeletal health of trans youth is an emerging focus.

Keywords: Adolescent contraception; Adolescent trans health; Anorexia nervosa; Estrogen; Peak bone mass; Primary ovarian insufficiency.

Figure 1

(A.) Mean percentage change from screening in the femoral neck BMD. (B.) Mean percentage change from screening in the lumbar spine BM.

Figure 2

Z scores for lumbar spine, hip and femoral neck BMD in girls with AN (■) and healthy control subjects (▢). Girls with AN had significantly lowers z scores at each site than healthy adolescents. *P < .01; **P ≤ .001.

Figure 3

Percent change in lumbar bone mineral density (LBMD) in adolescent girls with anorexia nervosa (AN) randomized to placebo (AN E-) (black bars), girls with AN randomized to estrogen (AN E+) (gray bars) and normal weight controls (C) (white bars). AN E+ had significant increases in LBMD at 6, 12, and 18 months compared with AN E-. When compared with C, AN E- had significant decreases in LBMD at 6, 12, and 18 months, whereas AN E+ did not differ from C for changes in BMD over time. Analysis was performed for differences between means for pairs *P < .05.

Figure 4

Percentage of low versus Normal BMD. Bar graph demonstrating markedly higher percentages of low BMD, as defined as at least one BMD z-score <−2, in our cohort of transgender/gender diverse youth. Low BMD error bars denote 95% confidence intervals. Data are stratified by sex designated at birth and show that DMAB had a higher frequency of pretreatment low BMD than DFAB youth (0.30 ± 0.47 vs 0.13 ± 0.35, P = .0545). Horizontal reference lines indicate the expected 2.3% to have BMD z-scores <−2 in a normal distribution. BMD, bone mineral density; DFAB, designated females at birth; DMAB, designated males at birth.

Figure 5

Estimated marginal means and standard error of the mean of BMAD prior to and during 2 years of GnRHa administration in transgirls and transboys. Significant changes during the 2 years of GnRHa administration are indicated by an asterisk. Abbreviations: BMAD, bone mineral apparent density; FM, femoral neck; LS, lumbar spine.

Figure 6

Estimated marginal mean and standard error of the mean of BMAD prior to and during 3 years of GnRHa + gender-affirming treatment in transgirls and transboys. Significant changes during the 3 years of GnRHa + gender-affirming treatment are indicated by an asterisk.

Figure 7

This random-effects forest plot assessed the 24-mo weighted mean difference in mean absolute change from baseline in g/cm² for spinal areal bone mineral density (BMD) in adolescent-combined hormonal contraceptives (CHC) users and nonusers/controls.