ABOUT FEMARELLE® (DT56a)
MENOPAUSE SYMPTOMS & FEMARELLE®
BONE HEALTH SUPPORT:
*Health Canada has not approved Femarelle for vaginal atrophy. Using Femarelle for vaginal atrophy would be considered off-label use.
*Femarelle is not recommended for use in breast cancer patients.
Vaginal Health: Clinical Study: Vaginal Atrophy
A Prospective Study of DT56a (Femarelle®) for the treatment of Postmenopausal Vaginal Atrophy. Nachtigall M et al. Menopause book of abstracts of the NAMS 22nd Annual Meeting Sept 2011 (Article in process
Vaginal atrophy is due to prolonged low estrogen levels and affects10-40% of post-menopausal women. It may manifest as vaginal soreness, dryness, pruritus, dyspareunia, or bleeding on contact. Unlike symptoms such as hot flushes, vaginal atrophy does not diminish over time and often progresses in severity.
To investigate the effect of Femarelle® on vaginal atrophy, 12 post-menopausal women with vaginal atrophy (<5% superficial cells on cervical cytology) with at least one moderate-to-severe symptom (dryness-2, irritation-1, soreness-3, dysuria-0, Dyspareunia-5, bleeding with coitus-1) were recruited for a 12-week open-label pilot study. Femarelle® capsules were given 2X/day for 12 weeks. At each visit (0, 4 and 12 weeks) subjects had a vaginal atrophy assessment (speculum exam, maturation index, vaginal pH) and completed questionnaires on atrophy symptoms and quality of life (Utian Quality of Life- UQoL). At weeks 0 and 12, physical exams, pap smears, vaginal cultures, and blood work were also performed.
Results: All the 12 patients, who were extremely atrophic, reported a significant improvement in their most bothersome symptom. In all women a significant reduction in vaginal pH was measured from baseline of 7.7 ± 2.2 at baseline to 4.9 ± 1.4 at week 12 (p< 0.0001). (Figure 10)
A significant improvement was also found in the maturation index. Parabasal cells that were 100% at entry were 43% following 12 weeks of treatment, Intermediate cells were changed from 0 to 47% and Superficial cells that were 0 at entry, were 10% following 12 weeks of treatment with Femarelle® (all statistically significant, p< 0.001).
A significant improvement was found in UQoL index from mean pre-treatment of 75.4± 22.7 points to mean post-treatment of 88.9± 26.8 (p< 0.001). In the sexual domains of the UQoL there was a significant improvement from 6.5 ± 2 points (mean pre-treatment) to 10.6± 3.2 (mean post-treatment) p< 0.001.
Conclusion: Femarelle® is a good candidate for the long term use during and after menopause; it provides both vasomotor symptom relief for the early menopausal women and relief of vaginal atrophy for the post-menopausal women, even for very atrophic conditions.6 Health Canada has not approved Femarelle® for vaginal atrophy. Using Femarelle® for vaginal atrophy would be considered off-label use.
Thrombogenicity: Clinical Study: Blood Clotting
The Selective Estrogen Receptor Modulator (SERM) DT56a (Femarelle) does not affect platelet reactivity in normal or thrombophilic menopausal women. Nachtigall L. et al. Menopause 2009
HT & ET increases clotting which can lead to venous thromboembolism (VTE) and stroke and thus cannot be given to women with shortened clotting time.
The frequency of inherited Factor V Leiden and other risk factors for VTE in the general population is estimated at 5-10%. This population has a 5-21 fold greater risk to develop VTE.
To investigate the effect of Femarelle® on the coagulation system, a platelet adhesion and aggregation device (PFA-100) was used. The PFA-100 measures the time for blood drawn through fine capillary to block membrane coated with collagen and epinephrine (CEPI) or collagen and ADP (CADP). This time is referred to as the closure time (CT), measured in seconds the clotting time of blood under flow. The PFA-100-measure of closure time is considered equal to clotting time in assessing clotting function and platelet adhesion, aggregation and blood coagulation factors.
The Platelet Function Analyzer - 100 (PFA-100) was used to assess the platelet reactivity at baseline and after eight weeks of treatment with Femarelle® in 25 symptomatic postmenopausal women with normal clotting times and seven symptomatic women with shortened clotting times (<61 seconds). Closure times were measured following 3 weeks, 8 weeks in all subjects and at one year in the women with shortened clotting times.
In two different clinical trials 116 symptomatic menopausal women were screened with the PFA-100 device. (Figure 16)
96 women were found to have normal clotting times (CEPI 85-165 sec. and CADP 71-118 sec.). From this group 29 women were placed on oral estrogen, 42 women on transdermal estrogen and 25 women with normal clotting times were treated with Femarelle® for 8 weeks.
13 women were found to have borderline clotting times (CEPI 70-84 and CADP 56-70 sec.); 5 were placed on oral estrogen and 8 on transdermal estrogen for 8 weeks.
7 women with short closure times (< 61 seconds) were excluded from administration of hormone therapy, and underwent a full thrombophilia work up. These women were subsequently treated with Femarelle®. Closure times were measured following 3 weeks, 8 weeks, and one year of treatment.
It was found that women with normal clotting time, who were placed on either oral or transdermal estrogen, showed no change in CT after 8 weeks of treatment. However, women who were borderline and treated with oral estrogen had a significant decrease in clotting time, while those treated with transdermal estrogen showed no change in CT13. (Figure 17)
Figure 17: CADP Closure Times with Oral or Transdermal Estrogen, in Women with Borderline Clotting Times
The Femarelle® group, with normal clotting time (n=25), showed no change in clotting time after three or eight weeks of Femarelle® therapy.
The seven women with shortened closure times (CEPI ÷ 60 sec and CADP ÷ 56 sec) confirmed abnormalities associated with thrombophilia (Table 3). No significant change in closure time was seen in this group after either three or eight weeks or one year of Femarelle® treatment (Figure 18)
Conclusion: Studies evaluating the incidence of VTE in women taking HT report the greatest absolute increase in the incidence of VTE shortly after initiation of therapy.14 Since none of the seven thrombophilic women had any change in clotting times after one year of treatment with Femarelle®, it points to the safety as regards to platelet function. Thus, Femarelle® offers a new clinical choice for menopausal symptom therapy without thrombogenicity.15
Breast Cancer: Pre-Clinical Study: Human Breast Cancer Tissue
Pharmacological Doses of the Natural phyto-SERM DT56a (Femarelle) Have no Effect on MCF-7 Breast Cancer Cell-Line. Yoles I., and Lilling G. European J. of Obstetrics & Gynecology & Reproductive Biology 2006
NOTE: Femarelle® is not recommended for use in breast cancer patients.
Estrogen-positive tumors account for 70% of all breast cancers. 21 A common model to examine the estrogenic activity of compounds is through MCF-7 breast cancer cell line. MCF-7 are estrogen dependent breast cancer cells.
Using this cell line, a study was carried out to determine whether Femarelle® (DT56a) has any estrogenic effect on the breast tissue.
MCF-7 cells were seeded and incubated for 96 hours in estrogen-depleted medium, and were then incubated with Femarelle® or E2 for 72 hours. The pharmacological dose of E2 was added to the cultured cells. Femarelle® was added in incremental doses, starting with the calculated pharmacological dose and increasing to 66,000 times the pharmacological dose.
Results: Unlike E2, Femarelle® did not stimulate estrogen receptors in the breast tissue, and therefore did not induce proliferation of cancer cells (Figure 15).
Conclusion: Femarelle® does not trigger breast cancer cell growth. This finding further supports the accumulating data verifying the activity of Femarelle® as a SERM.12 Femarelle® is not recommended for use in breast cancer patients.
Toxicology: Pre-Clinical Study: Toxicology
Femarelle lacks peripheral estrogen-like actions in the rat reproductive tract. Oropeza M.V. Orozco S., Ponce H., Campos M.G. Reproductive Toxicology 2005
A toxicity study failed to show any secondary estrogenic effects of Femarelle® on the estrogen-dependent characteristics of the female reproductive tract in a post-menopausal model of OVX rats. In that study, OVX adult female rats were randomly treated for 14 days with a placebo or with a low or high dose of E2 or Femarelle®. The low dose was calculated as 3 times the recommended dose (RD) and the high dose was 9 times the RD.
Uterine weight, keratinization of the vaginal lining, and sensitivity of the uterine smooth muscle to serotonin were monitored.
Results: Unlike E2, Femarelle® did not display any estrogenic effect on the uterine weight (Figure 20) or any sensitivity to serotonin (Figure 21). Compared to rats treated with E2, the vaginal lining of Femarelle-treated rats showed a small degree of keratinization.
Conclusion: The above findings show that Femarelle® has no estrogenic effects on the uterus.17
Summary: Femarelle as a SERM
Summary of documented research from referenced studies on this site and in our clinical data review.
The clinical and pre-clinical evidence presented in this clinical data review have shown Femarelle® to act as a novel Selective Estrogen Receptor Modulator (SERM) that affects estrogen receptors only in specific sites, without affecting tissues where any change can have dangerous consequences.
Femarelle® taken twice a day (morning and evening) is effective in relieving menopausal symptoms and supporting bone health. Clinical research and experience have shown that relief of menopausal symptoms is felt, on average, within the first month of treatment. Three in four women report relief, with alleviation of hot flushes in 76%, relief of joint and muscle pain in 70%, and relief of headaches in 68% (the main symptoms associated with the menopause transition). These rates were statistically significant (P <0.01).4, 7, 19
Femarelle® was shown to be effective for vulvo-vaginal atrophy, a condition reported by 75% of postmenopausal women.6 More clinical studies are required to further understand Femarelle’s impact on the vaginal health of menopausal women. Health Canada has NOT approved the use of Femarelle® for the treatment of vulvo-vaginal health.
The effect of Femarelle® on bone showed a statistically significant increase of 2.0% of BMD in the hip and of 3.6% in the spine after 12 months of treatment. The positive effect of Femarelle® on bones was also demonstrated in animal models.7, 11 Femarelle® offers support to the bone health of menopausal women.
These clinical results were achieved without causing changes in clotting parameters, the hormonal blood profile and without leading to any change in endometrial thickness or other changes in the uterus. 4, 7, 9, 15, 18, 19
A study of its mechanism of action on BMD in human bone cultures showed that Femarelle® exhibits unique bone-forming properties by increasing bone formation through osteoblast activity, while detaining the development of fat cells content in bone marrow, thus inducing bone rejuvenation.10, 11 Since Femarelle® acts differently than E2 in high Glucose environment; it may be an effective bone restoring agent in diabetic post-menopausal women that helps to support bone health.16
In a human breast cancer tissue culture study, Femarelle® had no effect on breast cancer tissue.12 Femarelle® is not recommended for use in breast cancer patients.
The positive effect of Femarelle® on the brain neurosteroidogenesis and the opiatergic system, may in part, explain the clinical effect of Femarelle® on menopausal symptoms.5
The unique active complex in Femarelle® represents a novel and effective treatment. There are no other chemically similar treatments for human use. The selective mechanism of action of Femarelle® enables it to act as an agonist on the estrogen receptors and thus, to exert a favorable effect on menopausal symptoms (hot flushes and sleep disturbances) and to support bone health while having an antagonistic effect on the estrogen receptors in breast tissue and in the uterus.
The efficacy of Femarelle® was seen to parallel the efficacy of Hormone Therapy, however, due to its selective properties, Femarelle® provides a safe solution for the long-term management of menopause.19
For all these reasons, Femarelle® is therefore, an appropriate first-line safe and effective therapy for the treatment of menopausal symptoms and to support bone health.