Raul Raz
Infectious Diseases Unit, Afulu, and the Technion Faculty of Medicine, Haifa, Israel.
Professor Raul Raz, Infectious Diseases Unit, Haemek Medical Center, Alula, Israel ; E-mail: [email protected].
Abstract
Urinary tract infection (UTI) is the most common bacterial infection m women, and it occurs with much greater frequency among elderly than among younger women and with increasing frequency among postmenopausal women In young to middle- age women, the prevalence of UTI is <5%, rising considerably with advancing age Epidemiologic studies have shown that ~15%-20% of 65- to 70-yeai old women have bacteriuna, compared with ~20%-50% of women >80 years old [1].
Despite the high prevalence of bactenuria among postmenopausal women, the factors predisposing such women to UTI have not been explored adequately as compared with those for premenopausal women However, it has been shown m an epidemiologic and clinical case-control study that nonsecretory status and urologie factors, such as residual volume, reduced urinary flow, previous urogenital surgery, incontinence, and cys- tocele, are strongly associated with recurrent UTIs m postmenopausal women [2] Another important factor related to recurrent UTIs is the lack of estrogen, which occurs during menopause, the period starting 1 year after the last menstruation and a time that is expected to encompass one-third of a woman’s life.
Current Knowledge
Estrogen and the urogenital tract Naturally occurring estrogens are 18-carbon steroids characterized by an aromatic a ring. The principle estrogen secreted by the ovary is estradiol, and it is also the most potent estrogen. Estrone is also secreted by the ovary, but most is formed by extraglandular conversion of androstenedione m penpheral tissues Although levels remain stable after menopause, the amount is insufficient to maintain premenopausal circulating levels of estrogen Estnol, the mam estrogen in urine, arises from the hydroxylation of estrone and estradiol [3].
The distal vagina and urethra share a common embryologie origin and are subject to similar hormonal influences, both being richly supplied with estrogen receptors. Estrogen receptors m the lov er urinary tract have been identified m the trigonal area, the epithelium lining of the urethra, and the vascular complex in the urethra submucosa. In premenopausal women, colonization of Enterobactcriaceae m the vagina After menopause, the vagina is eharaeteri/ed by different degrees of atrophy, clinically manifested as a syndrome consisting mainly of vaginal dryness, itching, irritation, and dyspareuma; recurrent IJTIs and urinary incontinence are also disabling postmenopausal conditions [4]. More than 50% of women >60 years old have some degree of urogenital symptoms.
Exogenous estrogen restores these urogenital changes and clinical symptoms. However, the treatment of these complaints requires an estrogen with specific urogenital activity without producing endometrial proliferation [4] Although medium-potency estrogens, mainly estradiol and conjugated estrogens, clearly alleviate urogenital symptoms related to menopause, benefits may also be achieved by the use of low-potency estrogen formulations administered orally (estnol) or mtravaginally (estnol, dienestrol, or estradiol in very low doses).
Ethmylestradiol, w'hich is present in most oral contraceptive pills, and the so-called conjugated estrogens are classified as high-potency substances, having a slow metabolism and a iong- lastmg effect Estnol is a metabolic end product with a short retention time of the nuclear estrogen receptor m different target tissues It is classified as a low-potency estrogen and has a specific urogenital activity While estradiol and estrone bind equally strongly to endometrial and vaginal estrogen receptors, estnol binds selectively to vaginal and marginally to endometrial receptors. Therefore, estradiol and estrone induce endometrial proliferation, increasing the risk of endometrial carcinoma. and when they are prescribed, it is necessary to add cyclic progesterone to counteract the action of estrogen on the endometrium Women receiving these hormones will have vaginal bleeding However, the use of estnol does not induce endometrial proliferation and, therefore, the use of progesterone is not necessary In addition, because estriol is an end product, its administration does not influence the level of other estrogens Estriol can be given orally or locally via vaginal cream or pessaries Peak levels of estnol are lower when administered orally rather than vagmally due to the first-pass effect of the liver Estrogen therapy in the prevention oj recurrent UTI Atrophy of the urethral epithelium and the trigonal area m the bladder and some degree of urge incontinence can also be alleviated with vaginal estrogen Kicovic et al [5] showed that vaginal estnol is efficient and safe for treatment of postmenopausal atrophic vaginitis and associated complaints. In addition, several small studies have shown that small doses of oral estriol reduced the incidence of UTI in postmenopausal women [6].
In 1993, it was demonstrated m a randomized, double-blind, placebo-control study, that vaginal estnol treatment had a dramatic effect on the incidence of recurrent UTIs m postmenopausal women [7]. In the study, it was shown that the incidence of UTI m women who received vagina estnol was reduced to 0.5 episodes per year, compared with 5 9 episodes pet year in women treated with placebo In addition, after I month, of treatment, lactobaeillus appeared in 60% of the estrogen-treated group but m none of those in the placebo group, and vaginal pH decreased from 5 5 ± 0.7 before treatment to 3 6 + 1.0 after treatment.
in 1999, similar results were presented by Eriksen [8]. using an estradiol-releasing vagina rmg In that study, the women m the estradiol group had a considerable reduction in the frequency of urogenital symptoms, such as vaginal dryness, dys- pareuma, and urge and stress incontinence, and after 36 weeks of study. 45% of the women receiving estradiol remained free of UTI, m contrast to 20% of the women treated with placebo Vaginal pH was also rcducec by the local estrogen therapy Maloney [9] also showed that topical replacement of vaginal estrogen m female nursing-home inhabitants reduced urogenital symptoms, vaginal pH, and the number of new episodes of UTI hi conclusion, estrogen replacement is effective not only m the tieatment of urogynecological symptoms ielated to menopause but aho in the prevention of recurrent UTIs Younger postmenopausal women can benefit from oral hormonal therapy, which improves clinical symptoms related to menopause and helps avoid osteoporosis and ischemic heart disease, the use of vaginas estrogen should be limited to women =>60 years old for the treatment of atrophic vaginitis, recurrent UT Is, and urge incontinence
Indications and contiumdicatums for estrogen therapy
Figure 1 summa' izes the indications and contraindications for es-trogen therapy. 'I he contraindications for the use of hormone replacement therapy (HRT). including caidiovascular diseases, diabetes, live disease, otosclerosis, endometriosis, melanoma, and hormone-dependent tumors, had been taken from the data sheets of oral contraceptives, and oral contraceptives are derived from alkylestrogcns. which are very diffeient from the estenzed or mierotu/ed estrogen used tn HRT. In other words, to my knowledge, no data regarding the risks associated with the use of HRT m postmenopausal women have been recorded.
Figure 1. Indications and contraindications for cslioger therapy UTI, urinary tract infection.
However, the use of HRT, including vaginal therapy, is absolutely contraindicated in women with active venous thromboembolism, severe active liver disease, and endometrial and breast carcinoma but can be administered to women with diabetes, gallstones, and other relative contraindications
Commentary
Questions and concerns regarding estrogen therapy- Two questions have been raised regarding the use of prolonged estrogen therapy m the prevention of UTI m postmenopausal women. First, what is the potential carcinogenic effect of estrogen? Second, can estrogen theiapy replace prolonged antimicrobial chemoprophylaxis, which is considered the reference standard m the prevention ot UTI in women0
In addition, the efficacy and safety of oral versus vaginal estnol treatment must be determined Estnol, has been used for more than 4 decades and has been regarded as ail estrogen that does not cause endometrial cancer However, Weiderpass et al. [10] showed in an epidemiologic case-control study that oral but not vaginal treatment with estriol increased the relative risk of endometrial proliferation and carcinoma. The authors speculate about a possible explanation of this phenomenon; however, they did not find a reason for the increase of endometrial hyperplasia and carcinoma m women receiving oral estnol, and they suggested that oral estnol therapy must be combined with a progestagen preparation.
The efficacy and safety of estriol compared with prolonged antimicrobial chemoprophylaxis m postmenopausal women with recurrent UTIs, was recently assessed in a double-blind dummy comparative study, m which 200 women received vaginal estnol twice weekly oi macrocrystals of nitrofurantoin daily during 9 months The results and conclusions are not yet complete and will be published m the near future.
Conclusions
Low-potency estrogens have been shown to be effective not only in the improvement of urogenital complaints related to estrogen deficiency but also m the prevention of recurrent UTI in postmenopausal women The safety and the comparative efficacy of both oral and vaginal estriol should be evaluated m future studies.
References
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Raz R, Gennesin Y Wassci J et al Recurient urinary tract inlectiors n
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Kirkengen Al , Andersen P Gjersoe F, Johannensen GR, Johnson N, Bodd L Oesterio'm the prophylactic treatment ot recurrent l H1 m postmeno-pausal women Scand J Prim Health Care 1992,10 139 42
Raz R, Stamm W À controlled tnal ol mtravagmal estnol m postmenopausal women with recurrent Lit nary tract infections N Fngl j Med 1993,329 753-6
S Fnksen BC A landomized. open, pmallel-group study on the preventive cited oi an estradiol-releasing vaginal ring (Fstring) on recurrent unrary tract infections in postmenopausal women Am J Obstet Gynecol 1999, 180 1072- 9
Maloney C Hoimime replacement therapy m fema.e nursing home residents w.th recurrent iinn^rv tract infection Ann Î ong-TeimC are 1998 6 77 83 10 Weicerpc.ss Baron JA, Adam IK), et al Low-potency oestiogen and risk of endometrial «.aneer a ease-control study 1 ancet 1999,353 1824 8