Early-to-mid gestation fetal testosterone increases right hand 2D:4D finger length ratio in polycystic ovary syndrome-like monkeys

Abstract

A smaller length ratio for the second relative to the fourth finger (2D:4D) is repeatedly associated with fetal male-typical testosterone (T) and is implicated as a biomarker for a variety of traits and susceptibility to a number of diseases, but no experimental human studies have been performed. The present study utilizes the rhesus monkey, a close relative of humans, and employs discrete gestational exposure of female monkeys to fetal male-typical T levels for 15-35 days during early-to-mid (40-76 days; n = 7) or late (94-139 days; n = 7) gestation (term: 165 days) by daily subcutaneous injection of their dams with 10 mg T propionate. Such gestational exposures are known to enhance male-typical behavior. In this study, compared to control females (n = 19), only early-to-mid gestation T exposure virilizes female external genitalia while increasing 2D:4D ratio in the right hand (RH) by male-like elongation of RH2D. RH2D length and 2D:4D positively correlate with androgen-dependent anogenital distance (AG), and RH2D and AG positively correlate with duration of early-to-mid gestation T exposure. Male monkeys (n = 9) exhibit a sexually dimorphic 2D:4D in the right foot, but this trait is not emulated by early-to-mid or late gestation T exposed females. X-ray determined phalanx measurements indicate elongated finger and toe phalanx length in males, but no other phalanx-related differences. Discrete T exposure during early-to-mid gestation in female rhesus monkeys thus appears to increase RH2D:4D through right-side biased, non-skeletal tissue growth. As variation in timing and duration of gestational T exposure alter male-like dimensions of RH2D independently of RH4D, postnatal RH2D:4D provides a complex biomarker for fetal T exposure.

Figure 1. Right hand (RH) finger parameters in adult control and early (EPA) and late (LPA) prenatally androgenized female and male rhesus monkeys.

(A) RH 2D finger length (^a p<2.9×10⁻⁴, Control<Male; ^b p<0.041, EPA>Control; ^c p<0.012, LPA<Male), (B) RH 4D finger length (^d p<3.6×10⁻⁴, Control<Male; ^e p<3.6×10⁻⁴, EPA<Male; ^f p<0.002; LPA<Male), (C) RH 2D∶4D ratio (^g p<6.6×10⁻⁴, EPA>Male; ^h p<0.009 EPA>Control Female; ^I p<0.016, EPA>LPA), (D) relationship between RH 2D finger length and anogenital distance (all groups, dashed line: r² = 0.76, p<1.0×10⁻⁶; females only, dot-dash line: r² = 0.79, p<1.0×10⁻⁴; 95% Confidence Interval (CI), solid lines), (E) relationship between RH 4D finger length and anogential distance (all groups, dashed line: r² = 0.65, p<5.7×10⁻⁵; females only: n.s.; 95% CI, solid lines), (F) relationship between RH 2D∶4D ratio and anogenital distance (all groups: n.s.; females only, dot-dash line: r² = 0.79, p<6.3×10⁻⁴; 95% CI, solid lines), (G) relationship between RH 2D finger length and duration of gestational exposure to testosterone propionate (Control and EPA females only, dotted line: r² = 0.62, p<6.0×10⁻⁵; 95% CI, solid lines), (H) relationship between RH 4D finger length and duration of gestational exposure to testosterone propionate (Control and EPA females only: n.s.), and (I) the relationship between RH 2D∶4D ratio and duration of gestational exposure to testosterone propionate (Control and EPA females only: n.s.). Horizontal dashed lines indicate range of control female values (G–I).

Figure 2. Right foot (RF) toe parameters in adult control and early (EPA) and late (LPA) prenatally androgenized female and male rhesus monkeys.

(A) RF 2D finger length, (B) RF 4D finger length (^a p<9.0×10⁻⁴, Control Female<Male; ^b p<0.002, EPA<Male; ^c p<0.011, LPA<Male), and (C) RF2D∶4D ratio (^d p<0.02, Control Female>Male; ^e p<0.04, EPA>Male).

Figure 3. Female anogenital distance positively correlates (Control and early prenatally androgenized (EPA) females only, dotted line: r² = 0.97, p<1.0×10⁻⁶; 95% CI, solid lines) with duration of early-to-mid gestation fetal T exposure.

Horizontal dashed lines indicate range of control female values.