Nipple and Areolar Hyperpigmentation Secondary to the Use of Estradiol Spray on the Ipsilateral Forearm Skin: A Report of Two Cases

Abstract

Estradiol transdermal spray can have the rare side effect of ipsilateral nipple and areolar hyperpigmentation. The time of onset can vary.

Androgenic and estrogenic indices in human newborns and infants: the MIREC-ID study

“…We found positive associations between VMI and areolar pigmentation in girls, supporting the notion that both measures are responsive to estrogen exposure. 15,19,39,48,49 This further serves to position the VMI as a reliable index of estrogen exposure, as has been shown in several prior studies examining differences in the vaginal maturity index of infant girls in response to soy (rich in phyto-estrogens) v. breastmilk. 14,48,50 Greater exposure to estrogens, most commonly related to pregnancy, has been previously associated with increased pigmentation in several nongenital locations, including in the ring of pigmented skin surrounding the nipple (areola), as well as the face and midline of the abdomen (linea alba).…”

“…14,48,50 Greater exposure to estrogens, most commonly related to pregnancy, has been previously associated with increased pigmentation in several nongenital locations, including in the ring of pigmented skin surrounding the nipple (areola), as well as the face and midline of the abdomen (linea alba). 39 There are also several reports of nipple and areolar hyper-pigmentation following the use of estradiol spray, 19,20 supporting the notion that areolar pigmentation may be sensitive to estrogen exposure. 39 Interestingly, smaller 2D:4D ratios and higher AGD-fourchette measurements (both hypothesized to represent higher androgen exposure) were associated with areolar pigmentation in girls.…”

“…Because the sexual maturation process is dependent on exposure to sex steroids, 7,8 measures of genital and sexual development such as anogenital distances (AGD), penile length/width and vaginal maturation index (VMIthe degree of maturation of vaginal wall cells) represent putative androgenic or estrogenic markers. [9][10][11][12][13][14][15][16][17][18][19][20][21] Similarly, the pigmentation of genital areas (e.g., vulva and scrotum), as well as that of other sexualized organs such as the nipple-areolar complex, represents additional measures of sexual maturation thought to vary with sex steroid levels. [21][22][23] Finally, metacarpophalangeal growth, as measured by the 2nd-to-4th digit ratio (2D:4D), is another process that has been shown to be quite sensitive to intra-uterine sex steroid exposure.…”

“…[24][25][26][27][28][29][30] For all of the aforementioned parameters, a rise in sex steroid levels is expected to lead to a similar, incremental, linear change in the hormonal markereither as an increase or a decrease in that specific parameter, 31,32 based on both molecular and clinical studies of animal and human samples. [9][10][11][12][13][14][15][16][17][18][19][20][21] One marker may be positively correlated with androgen exposure and negatively correlated with estrogen exposure (e.g., AGD 11,12 ), and another positively correlated with estrogen exposure and negatively correlated with androgen exposure (e.g., 2D:4D 12,25,27,30 ). Therefore, a given hormonal marker may both be categorized as an androgenic AND estrogenic index.…”