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.

Correlation between Digit Length Ratios and Risk Factors Associated with Metabolic Syndrome

“…The weaker relationship between the 2D:4D ratio of the left hand compared with that of the right hand with any of the parameters measured may be explained, at least partially, by findings from other studies suggesting differences between the left and right hands regarding apparent fetal androgen exposure. There are reports in the literature illustrating that the relationship of fetal androgen exposure to the 2D:4D ratio is stronger between digit measurements of the right hand compared to the left [9,13]. The stronger association of the right hand 2D:4D ratio with various traits assumed to be impacted by in utero androgen exposure is in line with previous findings where masculinizing traits are found to be more pronounced on the right side of the body [13].…”

“…PCOS is the number one cause of infertility in premenopausal women, and frequently women with PCOS have metabolic diseases such as hypertension and insulin resistance [1]. Interestingly, treatment of various animals prenatally with testosterone produces the metabolic as well as reproductive disorders associated with PCOS [2][3][4][5][6][7][8][9]. The metabolic defects associated with prenatal androgen exposure are not limited to females, but are also seen in males [2,10,11].…”

Adult digit ratio (2D:4D) is not related to umbilical cord androgen or estrogen concentrations, their ratios or net bioactivity

“…Further, it is uncertain when in gestation digit ratio is established. Experimental data has indicated that supraphysiological androgen exposure in early, but not late gestation, increased the length of the second digit and had no effect on the fourth digit in female rhesus monkeys, thereby resulting in a less male-like ratio [1]. Conversely, in female mice, in utero exposure to supraphysiological concentrations of the potent androgen dihydrotestosterone or a blocking estrogen action increased the length of the fourth digit, but had no effect on the second digit, resulting in a more male-like digit ratio pattern.…”

Male infants with hypospadias and/or cryptorchidism show a lower 2D/4D digit ratio than normal boys

“…Manno30 has shown that the correlation between prenatal androgen level and digit length in mice is more complex to assess and to explain than a direct relation, though other studies have shown the opposite 15. In monkeys, for instance, the results observed in subjects exposed to early testosterone levels during pregnancy are more nuanced than the results in mice 31. They do however confirm the influence of sex hormones on digit growth and genital development in primates.…”