Topical Alpha-1 Adrenergic Receptor Agonist Applied to the Nipple/Areola Complex Improves Female Orgasmic Function

Introduction

The nipple/areola complex (NAC) is an often overlooked and underestimated part of the female sexual response. Historically, Kinsey et al. minimized the importance of breast and nipple stimulation in the overall sexual responsivity of the female, noting that it was primarily a male to female sexual activity in the early stages of a sexual liaison. ¹ A study by Levin and Meston challenged this paradigm by demonstrating the importance of breast and nipple stimulation in female sexual arousal. ² In their study, 82% of women surveyed reported that stimulation of their nipples caused or enhanced their sexual experience. While not as pronounced as in women, 50%–60% of men also reported that nipple stimulation caused or enhanced their sexual arousal. ² In addition, Komisaruk et al. reported that nipple self-stimulation activated the genital sensory cortex, as well as the thoracic region of the homunculus map. ³ Also, stimulation of a woman's nipples has been shown to correlate with increased oxytocin levels in blood serum. ⁴ Oxytocin is a peptide hormone shown to play an excitatory role in the neurobiological paradigm for sexual function, ⁵ however, it was not shown to be an effective pharmacological treatment for female sexual dysfunction (FSD). ⁶

Conversely, the influence of reduced NAC sensitivity following breast reduction has been recognized and reported in the cosmetic and reconstructive surgery communities. ^{7 –9} Garcia et al. monitored women prospectively after reduction mammoplasty. The study demonstrated an association between sexual dysfunction, measured with the validated female sexual function index (FSFI), and low NAC sensitivity to temperature and pressure. ⁹ Other literature has documented changes in sexual function in women who have undergone reduction mammoplasty. ^{10 –12} Accordingly, we hypothesized that increasing NAC sensitivity could enhance female sexual function.

The smooth muscles of the NAC are innervated by adrenergic nerves, ¹³ as such, topical application of an alpha-adrenergic receptor agonist or a norepinephrine-releasing agent can stimulate nipple erection. It was our belief that inducing nipple erection would increase NAC sensitivity and could lead to positive benefits in female sexual function. In the following communication, we report the results of two efforts to explore this hypothesis. In the first study, nipple sensitivity changes after the application of a topical alpha-1 adrenergic receptor agonist (phenylephrine hydrochloride) are reported in a cohort of 13 women who reported deceased NAC sensitivity after breast surgery. In the second pilot study, changes in sexual function were assessed in a cohort of 35 women using a norepinephrine-releasing agent, RJ101, or a matched placebo 30 minutes before sexual activity. In the second study, selected domains of the FSFI and a rating of overall orgasm were used to assess sexual function changes over the 4-week trial period.

Materials and Methods

Thirteen breast augmentation patients ages 18 and older were recruited from the principal investigator's patient pool. Subjects had reported nipple sensitivity loss following breast surgery. All subjects gave informed consent before inclusion in the trial. Nipple sensitivity to pressure was measured at baseline using a set of seven Semmes/Weinstein filaments (0.07, 0.4, 1.0, 1.4, 2.0, 4.0, 10.00 g). The filaments were applied to each quadrant of the areola and the nipple (Fig. 1) in a stepwise manner, starting with the smallest fiber (0.07 g) and increasing fiber weight until the subject reported feeling pressure. Each fiber was pressed to the NAC location, being measured until it was bent. All subjects were measured by the same operator, to ensure data consistency. The time required to measure each quadrant with a single fiber was ∼1–2 seconds.

OPEN IN VIEWER

FIG. 1.

Quadrants of the areola (P1–P4) and the nipple (P5).

After the baseline measurement, a 10% phenylephrine hydrochloride solution was applied to the NAC with a cotton swab. Sixty minutes following the application of phenylephrine, the pressure sensitivity measurement was repeated. After the first visit, each subject was provided with a 5 mL dropper bottle of the phenylephrine hydrochloride solution. Each subject was instructed to apply the solution to the NAC ∼1 hour before sexual activity. Nipple sensitivity measurement data were collected again at 4 and 8 weeks after the initial visit.

In a follow-up exploratory study, 40 women ages 18 and older with normal NAC sensitivity were recruited to a randomized placebo-controlled study of RJ101, a novel formulation containing a norepinephrine releasing agent. Subjects included in the placebo-controlled pilot study did not participate in the first trial, that is, included subjects did not report reduced nipple sensitivity. Subjects were recruited from the patient pool of a sexual health practice. FSD was not a criterion for inclusion in the trial; however, a number of subjects had previously been diagnosed with FSD. All subjects gave informed consent before inclusion in the trial. At baseline, each subject completed the arousal, lubrication, and orgasm domains of the FSFI. ¹⁴ In addition, each subject rated satisfaction with their current orgasm on a Likert scale 1–10 (item satisfaction rating [SR], Table 2). The RJ101 solution and placebo were identically packaged in a single-use prewetted wipe. The investigator and participants were blinded as to which wipes were received. Study subjects were given a 4-week supply of RJ101 or placebo (eight wipes) and instructed to apply one wipe to both nipples 30 minutes before sexual activity at home. They were instructed not to modify or change their sexual repertoire or script. The questionnaire was administered again at 4 weeks.

Results

NAC sensitivity data are reported in Table 1. The average pressure measured in grams for each NAC is shown. Data 60 minutes after the application of the phenylephrine include the percentage decrease in grams shown in parenthesis, that is, the increase in sensitivity. The sensitivity measurement in grams at 8 weeks (t = 0) was lower than baseline (t = 0) sensitivity and on par with baseline (t = 60), indicating that intermittent application of phenylephrine to the NAC increased basal sensitivity.

In the follow-up placebo-controlled study using RJ101, 35 subjects completed the trial, 16 in the placebo arm and 19 in the RJ101 arm. The average age of the subjects was 43.2 and 44.8 in the placebo and RJ101 arms, respectively. The arousal, lubrication, and orgasm domains of the FSFI were used in addition to item SR, rating satisfaction with orgasm. Data from the 35-subject cohort are displayed in Table 2. The mean changes from baseline for each FSFI domain and item SR for the RJ101 group and placebo are reported in Table 3. A statistically significant difference between the RJ101 group and placebo was achieved in the FSFI lubrication and FSFI orgasm domains, p = 0.0226 and p = 0.0269, respectively. The mean change difference between the RJ101 group and placebo for item SR was found to be highly statistically significant, p = 0.0009.

Discussion

FSD is a prevalent problem affecting ∼43% of women. ¹⁵ FSD is classified as female sexual interest/arousal disorder, female orgasmic disorder, or genito-pelvic pain/penetration disorder. Often, a combination of these conditions is present in the same patient. At present, two drugs have been approved for the treatment of premenopausal women with generalized acquired hypoactive sexual desire disorder. Flibanserin (Addyi™) is a daily drug that acts on the central nervous system and caries a warning that limits concomitant use with alcohol. ¹⁶ Bremelanotide (Vyleesi™) is an as-needed injectable that is a melanocortin receptor agonist; in clinical trial, bremelanotide was generally well tolerated, with the main side effect being nausea (40%). ¹⁷ Considering that flibanserin requires chronic administration and is associated with serious adverse events and bremelanotide requires an injection, a safe and effective topical treatment would be an important advance in the pharmacological treatment of FSD.

The female breasts and nipples have been primarily recognized as a hormonally mediated organ that is associated with pregnancy and reproduction, that is, having a primary function to provide nourishment for the newborn. ¹⁸ In addition to nourishment, breastfeeding provides a hormonal tactile-mediated bonding experience for both the mother and infant via central oxytocin release. ¹⁸ Oxytocin is often thought of as the “cuddle hormone” and may facilitate human pair bonding.

Besides their reproductive function, many sociological and sexuality experts have recognized the breasts as being an important part of the sexual arousal paradigm. As such, the NAC should not be considered a secondary sexual response organ. Levin and Meston demonstrated the importance of breast and nipple stimulation. A short questionnaire was administered to 301 healthy subjects (148 men and 153 women) with an age range of 17–29 years. A total of 81.5% of women reported enhanced sexual response with breast and/or nipple stimulation, yet only 59.1% had asked their partner to stimulate their breasts/nipples during sexual foreplay. Only a small minority of women (7.2%) reported that stimulation adversely affected their arousal. ²

During breast surgery, many women report permanent or transient changes in sensation, including numbness or changes in nipple sensitivity. Djohan et al. demonstrated in his 8-year retrospective outcome study review that the majority of women who underwent a nipple-sparing mastectomy with immediate breast reconstruction were satisfied with the appearance, symmetry, color, position, and texture of the breast; however, more than 90% rated sensation as fair or poor. ¹⁹ In our first study, we have demonstrated that reduced NAC sensitivity can be treated with a topical alpha-1 adrenergic receptor agonist (phenylephrine hydrochloride). In our cohort of 13 women with nipple sensitivity diminished by augmentation surgery, we saw a 20% average increase in NAC sensitivity.

In our follow-up study of 35 women with normal NAC sensitivity, we saw statistically significant improvements in both the lubrication and orgasm domains of the FSFI when applying RJ101 to the NAC before sexual activity. We postulate that the effect may be due to a transient release of oxytocin. Nipple stimulation has been demonstrated to correlate with an increase in oxytocin and has been used as a method to induce labor in pregnant women. ⁴ Intranasal oxytocin administered to heterosexual couples has been reported to increased the intensity of orgasm, contentment, and sexual satiety in men. ⁴ However, Muin et al. reported no significant benefit of intranasal oxytocin over placebo in the FSFI score in a cohort of 30 FSD patients. ⁶ Alternatively, we theorize that the increase in sexual function may be due to a feedback mechanism or “reflex arousal,” that is, because sexual arousal erects the nipples, inducing nipple erection may signal the brain to increase overall sexual arousal.

Conclusion

For the first time, we demonstrate that the application of a topical alpha-1 adrenergic receptor agonist or a norepinephrine-releasing agent increases the sensitivity of the NAC and subsequently significantly improves sexual function. In our cohort, we demonstrated that increasing NAC sensitivity leads to positive benefits in the lubrication (p = 0.0226) and orgasm (p = 0.0269) domains of the FSFI. A limitation of this study is the small population sample size. In our cohort of women, there was a subpopulation of patients with FSD, however, the subject pool was too small to perform statistically relevant analysis. We plan to conduct screening for FSD in future trials to determine if these or other molecules in this class may have application as a treatment for FSD.