It is well known that estrogen alleviates symptoms of the menopause such as vasomotor disturbances and urogenital atrophy. Various articles have also attributed a protective effect on osteoporosis, cardiovascular disease and stroke as well as possibly Alzheimer’s disease. This view, with regard to protection against cardiovascular disease and stroke, has now been challenged by the Women’s Health Initiative study. It should be stressed that the combination of conjugated equine estrogens and medroxyprogesterone was perhaps not ideal, and additionally the women in this study were too old to allow assessment of primary protection. Various routes of delivering estrogen have been explored over the years: oral tablets, transdermal patches and gel, subcutaneous implants and the vaginal route via creams, tablets, pessaries and rings. The former three are more widely used by physicians. The reason for these different forms of hormone replacement therapy is that none of them are totally without problems. Table Advantages and disadvantages of different forms of hormone replacement therapy gives the advantages and disadvantages of the various methods. There are many reasons for discontinuation of hormone replacement therapy (Table Factors associated with non-use of hormone replacement therapy), and rates of discontinuation within 1 year vary between 20 and 60%. Up to 30% of patients do not even pick up their prescription from the pharmacy. It has also been recognized by many that some women require relief from, for example, urogenital symptoms without wanting to suffer the common side-effects of hormone replacement therapy such as the return of monthly bleeds and fear of cancer. A further 10-25% of women receiving systemic hormone replacement therapy with adequate control of symptoms such as hot flushes still suffer from the symptoms of urogenital aging.

Table Advantages and disadvantages of different forms of hormone replacement therapy

Advantages Disadvantages
Oral therapy
Easy to administer easy to forget
Easy to stop gastrointestinal side-effects
No accumulation variable absorption
Beneficial effect on cholesterol oral conversion to estrone
Wide choice of preparations more minor side-effects
Patches and gel
Easy to administer can be forgotten
Easy to stop occasional skin reactions
Avoids first-pass metabolism may come off accidentally
Beneficial effect on cholesterol more expensive than tablets
Released directly into bloodstream cosmetic effects poor
Physiological estradiol/estrone ratio  
Low-dose pure estradiol  
Implants
Guaranteed compliance minor surgery
Pure estradiol accumulation
Avoids first-pass metabolism pellet may need to be removed
Physiological estradiol/estrone ratio progestogen to be given orally
Testosterone can also be given possible tachyphylaxis

Table Factors associated with non-use of hormone replacement therapy

Safety concerns about effects on the breast, endometrium and thrombosis
Not medically recommended
Lack of information
Fear of weight gain
Fear of cancer
Bleeding and progestogenic side-effects
‘Unnatural’

Urogenital Aging

It is estimated that 10-40% of all postmenopausal women suffer from urogenital aging. Whereas vasomotor symptoms resolve over time, the climacteric symptoms of hypoestrogenic urogenital atrophy persist and often worsen. These are vaginal dryness, dyspareunia and symptoms from the lower urinary tract, including incontinence, urethritis and recurrent urinary tract infections. Women often do not associate these symptoms with the climacteric, as they can appear long after the menopause. More emphasis has been put on the prevention of osteoporosis and cardiovascular disease than on the alleviation of these local symptoms. The problem is compounded by the fact that women are often too embarrassed to discuss their symptoms openly, and it is of no help that sexual difficulties often complicate matters.

Clinicians experience difficulties in trying to treat older women, as they are less likely to tolerate side-effects of estrogen such as uterine withdrawal bleeding, breakthrough bleeding and breast tenderness. These occur especially at the doses of estrogen required to alleviate vasomotor symptoms. Furthermore, some women have contraindications to the use of systemic estrogens, yet should not have to suffer the debilitating symptoms of urogenital aging.

Older women are more likely to suffer from urinary tract infections owing to changes in the vaginal flora associated with the menopause. Estrogen in premenopausal women leads to colonization of the vagina by lactobacilli. This in turn leads to the production of lactic acid from glycogen, which maintains low vaginal pH with concomitant inhibition of organisms associated with urogenital infections. Estrogen also enhances pelvic blood flow, and thus the vaginal epithelium is kept healthy by the moisturization from an adequate transudate:.

Bearing all of this in mind, the issue of a possible role for locally administered vaginal estrogens has become a focus point.

Metabolism Of Estrogens

Cholesterol and its esters act as a substrate for steroid hormones, and the basic skeletons of these hormones are therefore similar. Cholesterol, through mediation by the cytochrome P-450, is converted into pregnenolone. This molecule is the precursor for ovarian steroidogenesis via a series of complex interactions of positive and negative feedback systems in the ovary, anterior pituitary and hypothalamus. The most important estrogen produced by the premenopausal ovary is 17β-estradiol. It is unique because almost all of it is synthesized in the granulosa cells from androgenic precursors derived from theca cells. The range of estradiol levels varies widely throughout the menstrual cycle. With age, ovulation becomes less frequent, with lower plasma levels of 17β-estradiol.

Estrone is the second major estrogen found in humans, and it is the principal estrogen of the menopause. It is formed mainly from the metabolism of 17β-estradiol and aromatization of androstenedione in adipose tissue. The estradiol/estrone ratio usually remains greater than 1 during the menstrual cycle. After the menopause, this ratio changes, as 17β-estradiol levels fall significantly whereas aromatization of androstenedione continues in adipose tissue. The estradiol/estrone ratio therefore reverses, and there is no deficiency of estrone.

The third estrogen found in women is estriol. It is not secreted by the ovary but thought to be a peripheral metabolite of estradiol and estrone.

During this metabolism of estradiol to estrone and estriol there is a reduction in estrogenic potency.

All these estrogens, estrone, estradiol and estriol, as well as synthetic estrogens are currently used as vaginal preparations.

Vaginal Estrogens

Estrogen is readily absorbed through the vaginal epithelium. However, it is true that although a daily dose of 50 µg of estradiol is necessary to relieve vasomotor symptoms, daily doses as low as 7-10 µg can produce relief of urogenital symptoms.

The reason for this absorption is the lipophilic nature of estrogens. Rapid absorption follows vaginal administration of estradiol, with minimal changes in estrone levels due to avoidance of the first-pass effect in the liver. This suggests very little metabolism of estradiol during absorption by the vaginal epithelium. Various studies have confirmed this. Martin and colleagues showed that 0.5 mg of micronized estradiol is absorbed rapidly and efficiently into the systemic circulation, without major conversion of estradiol to estrone as seen with oral estrogens. At this dose, the estradiol was absorbed systemically with suppression of gonadotropin levels. This confirmed the earlier findings of Schiff and associates. The question is, how much estrogen is needed to avoid systemic effects if this is indeed what is desired?

It is therefore necessary to take care when selecting the dose to be administered, as systemic absorption does occur except if the dose is very low. Nilsson and Heimer used vaginal tablets containing 10 and 25 µg of 17 (3-estradiol in a double-blind cross-over study. They found that maturation of the vaginal epithelium occurred with both doses, confirmed by cytology and use of the maturation index. There was no effect on plasma gonadotropin or estrone levels, but an initial rise in estradiol levels occurred in the first 6-8 h with decreased absorption as the vaginal epithelium became more mature. This confirmed the findings of Pschera and co-workers, who found that absorption was significantly higher in an atrophic vaginal epithelium. Handa and colleagues used low-dose vaginal estrogens (0.3 mg of conjugated estrogens, administered three nights a week for 6 months) and found satisfactory relief in 95% of cases. Vaginal cellular maturation improved significantly, and there were no significant changes in endometrial thickness or serum estrogen levels. Endometrial proliferation occurred in one case. Follow-up was 6 months, longer than in the Nilsson study. Weiderpass and co-workers found only a very weak association between vaginal application of low-potency estrogen formulations and relative risk of endometrial neoplasia in a population-based case-control study in Sweden.

Heimer and Samsioe argue that there is a therapeutic window where estrogens can relieve the symptoms of urogenital atrophy without stimulating the endometrium. Various possibilities for this unique response are discussed, but no definite answer has yet been found. The density of estrogen receptors in the vagina and paravaginal tissues is not high enough to explain this phenomenon, and it is not known whether functional status or a longer half-life of these receptors would explain it. Another possibility is that there is less attenuation of estrogenic potency through retarded metabolism in urogenital tissues, but even this possibility would not fully explain the differences in estradiol metabolism.

There are also problems with vaginal estrogens. Under-treatment leads to inadequate relief of symptoms, while over-treatment could lead to endometrial stimulation, despite the findings of Horwitz and Feinstein that there was no causal association between vaginal estrogens and endometrial cancer in two case-controlled studies. It is now widely accepted that Rigg and colleagues were correct in cautioning against the possible effects of vaginal estrogens on the endometrium. Other authors have demonstrated the systemic absorption of doses such as 1.25 mg of conjugated estrogens and 0.2 mg of micronized estradiol. In addition to the effects on the endometrium, creams, tablets and pessaries are also found to be messy, absorption is variable and administration intervals are irregular.

Estriol

Another option to avoid endometrial stimulation is usage of the weak estrogen estriol, which is believed not to be systemically absorbed or have endometrial effects because of its short half-life, probably due to shorter nuclear permanence. Its potency is also many times less than that of estradiol. Because of this short-acting effect, it does not appear to lead to cellular multiplication and differentiation or the synthesis of progesterone receptors. For this reason, estriol was studied to evaluate its effect on the vaginal epithelium. Bottiglione and co-workersshowed that there was no significant difference between 0.5 and 1.0 mg estriol in their effect on genital symptoms, but that there was a dose-related difference related to other symptoms of the menopause. Kikovic and associates showed that there was no endometrial stimulation after 16 weeks of treatment with estriol, but their number of patients was very small. Mattson and Cullberg confirmed these findings, although their follow-up period was only 8 weeks (and there was no control group in either of the above studies). They did, however, find subjective relief of urogenital symptoms in all the women in their study. They also showed estriol cream to be superior to suppositories as far as cervical mucus and vaginal cytology assessment was concerned. These studies and others showed very little effect of vaginal estriol on various hormones including luteinizing hormone, follicle stimulating hormone, prolactin, sex hormone-binding globulin and estradiol and estrone. Estriol levels initially rose sharply followed by a steady decline.

In a meta-analysis of estrogen therapy, Cardozo and colleagues found low-dose vaginal estrogens to be as effective as systemic therapy for the treatment of urogenital atrophy, with least absorption of estriol compared with estradiol and estrone.

In addition to symptoms associated with vaginal dryness, approximately one in every eight women over the age of 60 suffers from recurrent urinary symptoms. Raz and Stamm showed that 0.5 mg estriol cream intravaginally was superior to placebo in reducing this incidence of urinary tract infections.

Vaginal Rings

Another vehicle for delivering estrogen is the estradiol-releasing silicone vaginal ring. The reasons for trying to find an alternative method of vaginal administration have already been mentioned. A pilot study showed that two-thirds of hysterectomized women found a placebo intravaginal ring acceptable. All these women were taking alternative forms of hormone replacement therapy, and it could therefore be expected that a vaginal ring that actually contains hormones would be tolerated even better. Until recently the main use of vaginal rings was the delivery of low-dose estradiol (Estring ®). This ring was designed for a constant low release of 7.5 µg estradiol in 24 h. This intravaginal delivery system uses a soft, flexible silicone ring with a core section containing a 2-mg reservoir of 17β-estradiol. The surrounding silicone sheath acts as a diffusion barrier, which allows a uniform, sustained release of minute amounts of estradiol over 90 days. This leads to controlled local delivery with stable but low systemic levels of estradiol. Levels of estradiol remain comfortably within the normal postmenopausal range after an initial rise in the first 8 h. Henriksson and co-workers compared the use of a low-dose estradiol vaginal ring with 0.5 mg estriol vaginal pessaries. They found that both methods were equally effective in restoring the vaginal pH. Histopathological assessment of vaginal maturation showed the ring to be superior to the pessaries. Pessaries were also found to be significantly less comfortable than the ring, and patients previously using pessaries strongly preferred the ring. The same authors also showed Estring to be a highly effective and well-accepted mode of delivery in the long term for urogenital atrophy, over a period of 1 year. Other studies comparing use of the ring with various other forms of vaginal estrogens have also found results comparable, with satisfaction rates as high as 84% as reviewed by Bachmann. The same author reviewed 11 reports of clinical trials with the estradiol vaginal ring. The conclusion was that in 946 women treated with the ring for up to 96 weeks there was a good response regarding patient comfort and physical and cytological examination. No serious adverse events occurred and the ring was well tolerated. The greatest advantage, however, was that the ring was almost always significantly preferred to other forms of vaginal estrogens.

Furthermore, Eriksen compared users of Estring to an untreated control group in a randomized, open, parallel-group study to examine the effect of treatment on recurrent urinary tract infections. The vaginal ring was found to have a significant effect on prevention of recurrent infection. The mechanism by which this is explained is that estrogen restores the atrophic mucosa and increases the number of lactobacilli, thus leading to the cascade described previously.

The logical next step in development of the vaginal ring is investigating whether it will be suitable for the delivery of sufficient levels of estrogen to be used as systemic hormone replacement therapy. Nash and colleagues have addressed this issue recently after the concept was introduced in 1981. In the first study, three different doses of estradiol were used to determine whether sufficient levels in the effective estrogen replacement range could be reached in vivo. Relief of menopausal symptoms was reported in all women. Estradiol levels achieved were compatible with the control of menopausal symptoms as well as bone loss. There was also a significant reduction in total and low-density lipoprotein cholesterol. This study, however, was not placebo-controlled, numbers were small and the duration of treatment was very short.

The later study was conducted over a period of 6 months and showed a significant improvement in vasomotor symptoms and vaginal conditions. Again, there was no placebo arm.

Menoring ® (Galen), a ring delivering adequate levels of circulating estradiol for periods of 3 months to relieve a wide range of systemic symptoms, has recently been released.

Conclusions

Seen in the light of high discontinuation rates and patient reluctance to use systemic hormone replacement therapy, it would seem that vaginal estrogens have a role to play for postmenopausal women. That the use of hormone replacement therapy is certainly beneficial is a matter of education of the public, to remove often unnecessary biases against estrogen replacement therapy. Until such a time that clinicians and women are prepared to be more positive towards hormone replacement therapy, it would seem wrong not to treat the debilitating symptoms of urogenital aging. Certainly, the older woman with urogenital atrophy who does not wish to be subjected to the side-effects of systemic treatment would benefit from low-dose estrogens to alleviate very disturbing symptoms. This also applies to women in whom systemic treatment is contraindicated who wish to live a life without constant vaginal symptoms or urinary tract infections. The role is further extended to those women who need topping up of their systemic treatment. It is very important to remember that low-dose regimens are not an alternative to systemic hormone replacement therapy. If studies show that higher doses of estrogens with continuous combined progestogens offer the same advantages as other forms of hormone replacement therapy, this may well become an alternative form of replacement therapy with its own benefits. A vaginal ring capable of attaining adequate levels of systemic estradiol to offer all the advantages of such a treatment seems an entertaining idea, especially if concomitant progestogens can be administered via the same route. One particular factor that makes this form of administration appealing is that women can forget about hormone replacement therapy for periods of 3 months, yet still have enough control to remove the ring at certain times should they so wish. It should not be forgotten that hormone replacement therapy is an excellent form of preventive medicine with far more advantages than disadvantages. Any new idea that may therefore help to combat the high discontinuation rates or offer an alternative to women who cannot or do not want to tolerate current forms of administration should at least be considered.

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