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

Introduction

Estrogen administration has evolved from oral, vaginal, and injectable routes to estrogen-containing patches, gels, and sprays applied on the skin. Most recently, a metered-dose transdermal estradiol spray (Evamist, Ther-Rx Corporation) containing vehicle excipients that enhance the absorption of estradiol across the skin was developed for the treatment of postmenopausal vasomotor symptoms. ¹ Skin pigmentation is determined by genetic, environmental, and endocrine factors, which influence both melanin synthesis in melanocytes and the distribution of melanin throughout the epidermis. ² Reports from the literature have shown that the use of dermal ointments containing estrogens have resulted in the intense pigmentation of the genitals, mammary areola, and linea alba of the abdomen in both male and female infants ranging from 4 months to 2 years. ³ The nipple, areola, and linea alba show hyperpigmentation starting early in pregnancy. ⁴ We report two cases of unilateral pigmentation of the nipple and areola of two women following the application of estradiol spray (Evamist) to the ipsilateral forearm with varying times of onset of the pigmentation.

Case 1

A nulliparous 37-year-old white woman presented to a gynecology clinic with a complaint of discoloration of her left nipple and areola after using estradiol spray for 3 weeks. The patient had been prescribed the estradiol spray in order to treat vasomotor symptoms, dyspareunia, and vaginal dryness following a total abdominal hysterectomy and bilateral salpingo-oophorectomy in July 2007 for endometriosis. Prior to starting the estradiol spray, the patient's symptoms had been unsuccessfully treated with oral provera and an estrogen patch. The patient also had bilateral saline breast implants placed in June 2000. A recent mammogram of both breasts was normal.

On May 14, 2010, the patient initiated the use of estradiol spray (1.53 mg estradiol per spray) three sprays per day to her left forearm skin with improvement of her vasomotor symptoms. She noticed a change in the color of the left nipple and areola 21 days after first using the spray (Fig. 1). The patient used the estradiol spray every morning before getting dressed. Her breast exam in the clinic was normal except for the unilateral hyperpigmentation of her left nipple and areola and the anticipated findings of the bilateral breast augmentation. Her serum estradiol levels on June 13, 2010, were 65 pg/mL. The patient was reassured and was told that the hyperpigmentation of her nipple and areola was a benign side effect of the estradiol. She was advised to use the estradiol transdermal spray on her right forearm instead of the left. After 12 weeks of applying the same dosage of estradiol spray (three sprays per day) to the right forearm, her right nipple and areola also became hyperpigmented (Fig. 2). The left areolar and nipple pigmentation remained 3 months following the initial darkening. No topical treatments were given to the patient for the pigmentation. The patient continued using the estradiol spray to the right side forearm since the treatment provided relief of her symptoms.

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FIG. 1.

Case 1 after 1 week of left forearm estradiol therapy.

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FIG. 2.

Case 1 after additional 12 weeks of estradiol therapy to right forearm.

Discussion

These two cases illustrate the rare occurrence of hyperpigmentation of the ipsilateral areola and nipple with the use of estradiol spray on the forearm. The first patient used three sprays once daily for 3 weeks before the left-side hyperpigmentation was noted. The fact that the right areola and nipple pigmented after 12 weeks of daily use of three sprays per day to the right forearm suggests that the time of onset of the pigmentation is variable. In the second case, the patient used the transdermal estradiol spray three sprays daily for 6 weeks, which caused the ipsilateral nipple and areolar pigmentation.

It is theorized that the hyperpigmentation may be secondary to direct contact of the medicated forearm to the ipsilateral nipple and areola. Additionally, there could be an effect specific to the excipient to enhance absorption that contributed to the noted pigmentation.

In the first case, the reason that the left nipple pigmented much more quickly than the right side may be due to variable contact of the medicated forearm to the ipsilateral breast. The second case illustrates a longer period of use of the estradiol transdermal spray prior to the onset of hyperpigmentation of the nipple and areola.

There has only been one other reported case of ipsilateral areolar pigmentation following estradiol spray. ⁵ Diven and Crawford ⁵ postulated that the cause of the ipsilateral hyperpigmentation in the patient may be related to the shared venous and lymphatic drainage of the forearm and breast. The present report highlights that the ipsilateral areolar and nipple pigmentation can occur as quickly as 3 weeks after the start of estradiol spray treatment. Direct contact of the medicated forearm to the areola and nipple of the same side may be another reason for pigmentation on the ipsilateral nipple and areola. The patient in both cases retrospectively admitted that this may have occurred. The use of transdermal spray does not typically result in significant transfer of estradiol by skin to skin contact in adults. ⁶ The United States Food and Drug Administration (FDA) posted a special alert regarding “adverse effect on children and pets of women using transdermal estradiol spray.” ⁷ The alert recommends that “patients should make sure that children are not exposed to Evamist and that children do not come into contact with any skin area where the drug was applied. Women who cannot avoid contact should wear a garment with long sleeves to cover the application site.” This alert strongly supports transdermal absorption of Evamist by children and pets. Thus the ipsilateral pigmentation of nipple and areola after application of transdermal estradiol spray could be due to direct contact of the medicated forearm area to the ipsilateral areola and nipple.

In conclusion, ipsilateral pigmentation of nipple and areola after use of transdermal estradiol spray is a rare complication. Duration of onset of the pigmentation after usage of transdermal estradiol may vary and may be dose independent. The patients may seek help from a gynecologist, dermatologist, or family physician. Patients should be instructed to first put on clothes or a bra before using the estradiol spray to prevent direct contact of the forearm on which transdermal estradiol is applied to the ipsilateral breast. Reassurance to the patient experiencing hyperpigmentation can be offered along with the precautions advised by the FDA. Sunscreen can be applied 1 hour after application of estradiol spray. ⁶ Topical application of estradiol cream on the thigh verses the forearm did not result in any difference in serum estradiol levels after 3 months of use. ⁸ Thus, application of estradiol spray to the thigh could be another option to minimize contact to the nipple and areola.