Effect of E2 on bladder circulation

CFigs. 2C and D.
Legends, see the previous page.

Dthe duration of estrogen replacement, estrogen wasintroduced for 4 or 8 weeks to 2 different groups
for any consequence stemming from longer duration of treatment.
We observed plasma E2 levels lower than 15
pg/mL in Group IV. The fertility period of rats
lasts approximately until the age of 15 months, atwhich time the estrous cycle ceases (Handa et al.,
1987; Shulman et al., 1987; Albert et al., 1991).
According to Albert et al. (1991), rats with normal
body weights maintain the plasma E2 level slightly

below the mean of 15 pg/mL throughout the estrous
cycle. In the present study, we gave no estrogen replacement to Groups I and IV. The plasma E2 levels obtained from 16-month-old rats in Group I exceeded 15 pg/mL, slightly higher than expected atsuch an age. In Group IV, as expected, 18-monthold ratsʼ levels were slightly lower than 15 pg/mL.
Groups II and III received estrogen replacement,and their plasma E2 levels were significantly increased to more than 30 pg/mL and 40 pg/mL, respectively. Therefore, our E2-replacement method

87

K. Hikita et al.
provided adequate levels for studying its effects onrat bladders.
In a comparison to normal control rats, ovariectomized rats had a decreased bladder weightand increased body weight (Longhurst et al.,1992). Also in our observations, we found that
bladder weight was significantly heavier in GroupIII than Groups I and IV, while there were no significant differences in Group II compared to theother groups. However, Group II had a higher tendency of mean bladder weight than Groups I andIV. Thus, the bladder tended to gain weight when
the E2 level was increased, which suggests thatE2 replacement after menopause increases bladder weight. The bladder had been thought to gain
weight in muscle content and epithelium thickness(Rocha et al., 2002). We observed no significant
difference in mean body weight among groups,
but estrogen-replaced rats lost some weight. The
mechanism for how estrogen protects the bladderagainst collagen formation is not yet known. Someevidence suggests it has a cardioprotective action
preferably through nitric oxide from endothelial
release: estrogen replacement may prevent the proliferation of fibroblasts and collagen deposition in
the blood vessels of the heart (Blacher et al., 2000).
Whether a similar mechanism exists in the bladder
is a subject of further study.
The number of blood vessels influences intraurethral pressure (Versi and Cardozo, 1986). Estrogen replacement therapy was reported to increase
the number of periurethral and bladder vessels (Madeiro et al., 2001). In ovariectomized rats, however, the number of bladder vessels was decreased(Rocha et al., 2002). We observed no significant
differences in the number of bladder vessels amonggroups, but only a little increase in Groups II andIII. Estrogen acts directly on the number of bladdervessels in the urethra and periurethral tissue. Thisaction could explain the increase in the number ofbladder vessels due to estrogen replacement. Evenwith estrogen replacement, however, the increasein the number of bladder blood vessels was slightin our experiments: the increase in muscle content
and cell cycle activity might have acted together.

Estrogen treatment inhibits tissue weight gain
and cardiac output, and so blood flow of the urinary tract is also increased by estrogen (Batra etal., 1985, 1986). In this study, there was a significant difference in blood flow between E2-replacedgroups and the control and placebo groups. Estrogen increases blood flow as previously reported(Batra et al., 1986) as well as in the present study.
The slight increase in bladder blood flow we observed may be due to the increase in bladder weight
and overall blood volume (not measured in thepresent study). According to the literature, thecompliance functions of the bladder and urinarypressure are also improved with estrogen. These
improved functions also help improve circulation(Fleischmann et al., 2002). Our estrogen replacement therapy for mature rats resulted in an increasein bladder muscle content and blood circulation,
similarly as reported (Rocha et al., 2002).
In medical trials conducted since the 1960s
predominantly in the United States, menopausal
women have been given progesterone concurrently
with estrogen to protect against increased risks ofcancer. Studies in Japan have also shown estrogen useful in the treatment of stress incontinence(Suzuki et al., 1997). Since the present study has
shown the benefits and advance effects of estrogen
replacement therapy in rats, it should be advocatedas a treatment in general practice.

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Received September 13, 2004; accepted November 28, 2004
Corresponding author: Ikuo Miyagawa, MD

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