Estriol and Vulvovaginal Atrophy

moistureUrogenital atrophy (vaginal dryness and irritation) is often times inevitable among postmenopausal women especially if significant amount of time has elapsed being estrogen deficient. The vagina and urinary bladder are estrogen dependent organs that contain estrogen receptors within the epithelial lining. Prolonged estrogen deficiency significantly affects vulvovaginal health, sexual functioning, urinary health, and more importantly quality of life.

We are well aware that estrogen deficiency is a normal and ongoing progression related to the menopause transition and is the definite link to urogenital atrophy (thinning and dryness)

It has been well established that estrogen replacement therapy (ERT) is a logical choice of treatment for symptoms related to the thinning, irritation, pain and dryness associated with vaginal atrophy. While both systemic (oral) and local (topical/intravaginal) ERTs are effective in relieving vaginal dryness, vaginal itching, and dyspareunia; preventing recurrent UTIs; and reversing some of the signs of urogenital atrophy, low-dose local ERT appears to offer several distinct and important advantages over traditional oral replacement therapy, most importantly the lack of systemic effects.

Local vaginal estrogen products are available in cream, gels, estrogen containing rings, and intravaginal tablet formulations, all of which are extremely effective and well tolerated, although adherence rates to the ring and tablet regimens are slightly higher merely because the creams can be messier and more hygienically appealing. Of note is that estrogen compounded in a gel base (pleuronic gel) has seemed to revolutionize the applications of intravaginal sources because they appear to adhere to the vaginal walls more readily and appear to absorb quicker. As always the choice and duration of therapy should be individualized, depending on the needs and preferences of each woman.

INTRODUCTION
Estrogen deficiency is the cause and effect of urogenital atrophy in menopausal women. Atrophy causes progressive changes of the vagina, vulva, and urinary tract have a large impact on quality of life (QOL), as these symptoms historically worsen with time.
Common symptoms associated with urogenital atrophy include:

  • ladyvaginal dryness
  • irritation
  • itching/burning
  • burning with urination
  • spotting (usually bright red with wiping)
  • painful sexual intercourse
  • recurrent urinary tract infection (UTI)
  • urinary incontinence
  • pelvic organ prolapse
  • recurrent vaginitis/vaginal infections
  • narrowing of the vaginal opening
  • blending and diminished size of the labia
  • persistent yellow discharge with or without odor
  • lack of vaginal lubrication
  • decreased sensitivity with intercourse
  • decreased sensitivity and duration of orgasm
  • Urogenital atrophy occurs in 30%-60% of peri- and postmenopausal women.
  • More than 30% of postmenopausal women experience pain during sexual intercourse with most reporting lack of vaginal lubrication as the main issue surrounding it and causing many women to avoid or lose interest in sex.
  • About 10% of postmenopausal women aged 50-75 develop recurrent urinary tract infections (UTIs).
  • More than 60% of postmenopausal women are reluctant to openly discuss most of the issues surrounding the problem with their clinician, especially those symptoms related to sexual function.
  • Fewer than 25% of women with urogenital atrophy receive appropriate care for it.

Estriol- “The weakest of the weak appears to be the strongest of the strong.”

Historically estriol, is an estrogen that has virtually been an unknown in mainstream hormone replacement management. It is one of the three principal estrogens produced by the body. Estriol was originally thought to have little significance due to its weak estrogenic activity when compared with estrone and estradiol. Nonetheless, research has found that its weakness may very well be its strength.  Having weaker estrogenic effects does not mean that estriol has none of the benefits that come with more potent estrogens.

Studies suggest that estriol reduces symptoms of menopause, such as hot flashes and vaginal dryness, but with a better safety profile compared with more potent estrogens. This makes estriol one of better choice for bioidentical hormone-replacement for certain hormone imbalance issues.

Extensive peer review of well over 150 studies has clearly demonstrates that vaginal estriol is efficacious in resolving most if not all of the local vaginal and urinary symptoms associated with vulvovaginal atrophy.
Vaginal estriol, delivered in the correct dosage, has a proven safety profile, in addition to having no adverse affects on the vascular system, liver, endometrium or breast tissue. It has safely been used to treat symptoms in breast cancer patients. Estriol has been used in Europe for over 60 years (Puck 57, 60).

Efficacy & Safety of Vaginal Estriol

Estriol has a high relative binding affinity (RBA) for estrogen receptors in:

  • Bladder
  • Vaginal tissue

Because of the high RBA for the ER in the vaginal tissue and bladder, estriol will have a strong/beneficial effect in these tissues.

Estriol has a low relative binding affinity RBA for estrogen receptors in:

  • Uterus (myometrium)
  • Breast tissue
  • binds to the estrogen receptor in the breast tissue for a shorter period of time (6 hours)
  • Causes less of an effect than the more stimulatory estradiol and estrone which bind to the ER for a longer period of time, 24 hours
  • acts as a weak estrogen in the breast, endometrium and liver while having full estrogenic responses in the vaginal and bladder epithelium

Because of the low RBA for the ER in the myometrium and breast, estriol exerts only a weak effect in these tissues.

Estriol is much less stimulatory to the breast and endometrial tissue than ‘strong’ estrogens like estradiol, which have much higher RBA in these tissues.

Estriol acts as a selective estrogen receptor modulator

  • binding strongly to the ER in the bladder and vaginal tissue
  • and weakly to the breast and endometrial tissue.
  • Estriol: binds to the estrogen receptor in the breast tissue for a shorter period of time (6 hours)
  • Causes less of an effect than the more stimulatory estradiol and estrone which bind to the ER for a longer period of time, 24 hours
  • acts as a weak estrogen in the breast, endometrium and liver while having full estrogenic responses in the vaginal and bladder epithelium

Dosage and Pharmacokinetics
The doses and pharmacokinetics of vaginally applied estriol are well known.

Estriol is delivered as a vaginal cream or gel in a 0.5 to 1.0 mg dose.

  • Unlike oral estriol, which may accumulate, vaginal estriol does NOT accumulate
  • Vaginal estriol, like other hormones administered vaginally, shows consistent absorption without adverse effects on estrone and estradiol levels
  • Vaginal estriol, commonly delivered 0.5 mg daily for 14 days then 3 times weekly

Vaginal estriol also relieves urinary symptoms:

  • stress incontinence
  • dysuria
  • urgency
  • reduces the incidence of urinary tract infections

There is substantial peer reviewed data which supports that vaginal estriol relieves systemic menopausal symptoms including: hot flashes, night sweats and symptoms.

Vaginal estriol has also been shown to:

  • be superior to Premarin vaginal cream
  • relieve vaginal dryness, vaginal atrophy and dyspareunia
  • normalize vaginal flora
  • not affect clotting factors, cause fluid retention or weight gain
  • prevent bone loss and increase bone density
  • increase serum HDL, lower LDL
  • dilate blood vessels by activating the NO (nitrous oxide) system
  • prevent coronary artery disease by preventing plaque formation in blood vessels
  • have no adverse effect on blood pressure

Vaginal estriol delivered in the correct doses DOES NOT:

  • stimulate the uterine lining
  • cause uterine hyperplasia (abnormal thickening of the uterine lining)
  • increase in the incidence of uterine cancer

Estriol has a low RBA (Relative Binding Affinity) for estrogen receptors in breast tissue and a rapid dissociation from the estrogen receptor (6 hrs).

Estriol does not increase breast density

Estriol Safety- Effects of the breast and uterus

Vaginal estriol delivered in the correct doses DOES NOT:

  • stimulate the uterine lining
  • cause uterine hyperplasia (abnormal thickening of the uterine lining)
  • increase in the incidence of uterine cancer

Estriol

  • has a low relative binding affinity(RBA) for estrogen receptors in breast tissue
  • and a rapid dissociation from the estrogen receptor (6 hrs)
  • does not increase breast density

Major, large, peer reviewed trials have repeatedly shown that vaginal estriol does NOT increase the risk of breast cancer:

  • Million Women’s Trial 03 RR 0.67
  • Fournier 04
  • Rosenberg 06
  • Lyntinen 02
  • Bergvist 89

There is no data to the contrary.

Studies are mixed in regards to oral estriol and breast cancer, with the majority of trials showing no increase in the risk of breast cancer.

Conclusion
Peer reviewed data clearly demonstrates that vaginal estriol is efficacious for:

  • local vaginal urinary symptoms
  • and systemic menopausal symptoms.

Vaginal estriol, delivered in the correct dosage, has a proven safety profile.  There are no adverse affects of vaginal estriol to the vascular system, liver, endometrium or breast tissue.   It has safely been used to treat symptoms in breast cancer patients.  There is a lack of data supporting the use of topical estriol on skin.  ).