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     Vestibulodynia, also known as provoked localized vulvodynia and formerly termed the "vulvar vestibulitis syndrome," is characterized by a severe, burning/sharp pain that occurs in response to pressure localized to the vulvar vestibule. Painful intercourse (dyspareunia) as well as pain with tampon insertion are hallmarks of this condition. Although there are likely multiple causes of vestibular pain, the relationship to combined hormonal contraceptive (CHC) use is becoming increasingly recognized. Because CHCs inhibit luteinizing hormone, there is a decreased ovarian production of testosterone. In addition, both the synthetic estrogen and synthetic progestin component of CHCs, which are metabolized in the liver, leads to increased hepatic production of sex hormone binding globulin (SHBG).

 Burrows and Goldstein (Obstetrics and Gynecology, The Center for Vulvovaginal Disorders, Washington, DC) studied 50 consecutive premenopausal women with vestibulodynia who were using CHCs at the time they presented for care. All women previously had pain-free intercourse and had subsequently developed vestibular pain (i.e., secondary vestibulodynia). Patients who had other causes of vestibular pain such as pelvic floor muscle hypertonus, infection, and vulvar dermatoses were excluded from this review; thus, only patients in whom CHCs were the only identifiable cause of their vestibular pain were included. The average age was 26 years, and the average duration of CHC use was 7 years. The most commonly used CHHs were LoEstrin (n = 6), Yasmin (n = 6), and Yaz (n = 5). Vestibular pain scores decreased from 7.5 to 2.

   Per their standard practice, the physicians asked all patients to discontinue CHCs, and patients were asked to apply a compounded preparation of topical estradiol 0.03% and testosterone 0.01% to the vestibule twice daily. Baseline and posttreatment SHBG levels were 154 nmol/L and 64 nmol/L, respectively, and calculated free testosterone levels were 0.193 ng/dL and 0.813 ng/dL, respectively. The average duration of treatment was 20 weeks.

   The combination of lower total testosterone production from the ovaries combined with the increased levels of SHBG in turn lead to decreased levels of circulating free testosterone. It has been suggested that CHC with newer progestins lower free testosterone more than CHC with the earlier progestins.

  Results demonstrated that women with vestibulodynia who had no other identifiable cause of their pain that began while taking combined hormonal contraceptives achieved a positive treatment outcome by discontinuing the CHCs combined with the application of a compounded topical hormone therapy containing estradiol and testosterone. Furthermore, subjective improvement was accompanied by normalization of calculated free testosterone and SHBG values.

   Controversy exists about whether vaginal estrogens interfere with the efficacy of aromatase inhibitors (AIs) in breast cancer patients. With the greater incidence of vaginal atrophy in patients on AIs, Witherby et al. of Warren Alpert School of Medicine at Brown University, Providence, Rhode Island, searched for a nonestrogen therapy and hypothesized that vaginal testosterone cream could safely treat vaginal atrophy in women on AIs.

   Postmenopausal breast cancer patients on AIs with symptoms of vaginal atrophy were treated with testosterone cream applied to the vaginal epithelium daily for 28 days. Ten women received a dose of 300 micrograms and 10 received 150 micrograms daily,. Estradiol levels, testosterone levels, symptoms of vaginal atrophy, and gynecologic examinations with pH and vaginal cytology were compared before and after therapy.

   Estradiol levels remained suppressed after treatment to <8 pg/mL. Mean total symptom scores improved from 2.0 to 0.7 after treatment and remained improved 1 month thereafter. Dyspareunia and vaginal dryness improved. The median vaginal pH decreased from 5.5 to 5.0. The median maturation index rose from 20% to 40%. Although improvement in total symptom score was similar for both doses (-1.3 for 300 μg, -0.8 for 150 μg; p = .37), only the 300 microgram dose was associated with improved pH and maturation values.

   The physicians concluded that a 4-week course of vaginal testosterone was associated with improved signs and symptoms of vaginal atrophy related to AI therapy without increasing estradiol or testosterone levels. Longer-term trials are warranted.

   In the search for alternative agents to oral finasteride and topical minoxidil for the treatment of androgenetic alopecia (AGA), melatonin has been identified as a promising candidate based on in vitro and in vivo studies. Stressful influences such as UV radiation, smoking, and environmental pollutants lead to the formation of free radicals, resulting in damage to hair follicles. Melatonin may counteract the oxidative stress due to its strong anti-oxidant properties.

   Fischer et al. examined whether topically applied melatonin influences anagen and telogen hair rate in women with androgenetic or diffuse hair loss.. A double-blind, randomized, placebo-controlled study was conducted in 40 women suffering from diffuse alopecia or androgenetic alopecia. A 0.1% melatonin or a placebo solution was applied on the scalp once daily for 6 months and trichograms were performed to assess anagen and telogen hair rate. To monitor effects of treatment on physiological melatonin levels, blood samples were taken over the whole study period. Melatonin led to a significantly increased anagen hair rate in occipital hair in women with androgenetic hair loss compared with placebo. For frontal hair, melatonin gave a significant increase in the group with diffuse alopecia. The occipital hair samples of patients with diffuse alopecia and the frontal hair counts of those with AGA also showed an increase of anagen hair, but differences were not significant. Plasma melatonin levels increased under treatment with melatonin, but did not exceed the physiological night peak. This pilot study showed that topically applied melatonin 0.1%  might influence hair growth in humans in vivo.

  A Swiss company developed a topically applied cosmetic hair solution with a melatonin content of 0.0033%, which was intended to slow the hair's aging process and be used as an adjuvant treatment for AGA. Fischer et al. evaluated the benefits of daily use of this preparation in 35 men with AGA. A significant increase of hair density of 29% after 3 months and 41% after 6 months was measured in over half of the patients.

   In a large, 3-month, multi-center study with more than 1800 volunteers at 200 centers, the percentage of patients with a 2 to 3-fold positive hair-pull test following the use of topical melatonin decreased from 61.6% to 7.8%, while the percentage of patients with a negative hair-pull test increased from 12.2.% to 61.5%. The hair pull test helps evaluate scalp hair loss. If gentle pulling of 40 hairs results in loss of 4 to 6 with each pull, the pull test is positive.

  The authors concluded that topical application of a melatonin solution can be considered as a treatment option in androgenetic alopecia. In addition, a decrease in seborrhea and seborrheic dermatitis of the scalp was observed.

Br J Dermatol. 2004 Feb;150(2):341-5.

Int J Trichology. 2012 Oct;4(4):236-45.

   For 21 days post-radiation to the tongue, male Wistar rats were treated with 45 mg/day melatonin gel or vehicle, locally applied into their mouths. The application of melatonin gel restored physiological melatonin levels in the tongue and prevented mucosal disruption and ulcer formation. Melatonin gel protected the mitochondria from radiation damage and blunted the inflammasome signaling activation in the tongue, suggesting a potential preventive therapy for mucositis in patients with cancer.