Cost-effectiveness of perioperative vaginally administered oestrogen in postmenopausal women undergoing prolapse surgery.

Pelvic organ prolapse (POP) is a common disorder affecting about 40% of
postmenopausal women. Women with POP are bothered by a sagging sensation and
problems with micturition, defecation and sexual functioning. The body image of
these women is often negatively affected, and their loss of productivity can
have financial impact. Surgery is often indicated to relieve symptoms, but is
successful in only 70% of treated women since 30% needs surgery for recurrent
prolapse. The group of women in the postmenopausal age is growing rapidly, the
societal impact of this health problem is large and ways to improve treatment
outcomes of POP surgery is needed.

It has been shown that women with pelvic floor pathology benefit from vaginal
oestrogen therapy. A reduction of symptoms has been described in women with
stress urinary incontinence, overactive bladder symptoms, recurrent cystitis,
and prolapse symptoms after using vaginal oestrogen.Vaginal atrophy can be
solved by the use of vaginal oestrogen therapy, effectively treating bothersome
symptoms like vaginal dryness, and itching of the vulva. The hypothesized
underlying mechanism is that oestrogen results in a thickening of the vaginal
wall or urothelium, and improves vascularization of the pelvic floor. Apart
from the above described clinical evidence, there are basic scientific data
available that support this hypothesis. In our clinic, several studies have
been performed to investigate the potential beneficial effects of vaginal
oestrogen therapy. Using an objective outcome measurement, we showed that
vaginal wall thickness more than doubles within 6 weeks after start of vaginal
oestrogen supplementation. An randomized trial showed that the use of vaginal
oestrogen prior to prolapse surgery increased the production of collagen and
reduced degradative enzyme activity. Therefore, it is assumed that women with
low oestrogen levels who undergo surgery for POP have a higher risk of
recurrence of their POP symptoms because poor vascularization and a thin
vaginal wall compromise their healing capacity. Administering vaginal oestrogen
is expected to improve healing conditions and consequently reduce risk of
recurrence. Oestrogens act on the cutaneous wound healing response by
modulating the inflammatory response, cytokine expression and matrix
deposition. They also accelerate re-epithelialization, stimulating angiogenesis
and wound contraction, and regulate proteolysis.

Vaginal oestrogen therapy has been used in practice for over 30 years in 74
different countries and is considered to be safe. Although vaginally
administered oestrogen could result in a minimal systemic uptake, serum
oestrogen levels remain within the normal range for postmenopausal women.(19)
Also no endometrial or myometrial effects are seen with the use of vaginal
oestrogen. In literature, an increased risk of breast cancer or endometrial
cancer has never been proven for vaginal oestrogen therapy (only for systemic
use of oestrogen).
A review identified two studies that investigated the use of vaginal oestrogen
as compared to placebo or no treatment for treating POP. These studies show
that POP treatment with oestrogen led to a significant difference in POP
symptoms and in vaginal health composite score. Although there is benefit that
vaginal oestrogen therapy improves pelvic floor function following POP surgery,
and improves healing conditions, there is no comparative study to evaluate
whether vaginal oestrogen therapy before and after POP surgery improves
outcome. Based on the theoretical background, such study would need to be
performed in postmenopausal women as they have low levels of oestrogen. For
that reason, we propose a multicentre RCT comparing perioperative vaginal
oestrogen therapy to placebo in post-menopausal women undergoing vaginal POP
surgery.

Health care efficiency problem: Worldwide 30% of all POP operations is
performed for recurrent prolapse. The costs associated with the treatment of
recurrent POP are huge, and the burden by the women who encounter recurrent POP
has negative impact on quality of life. Oestrogen has a proven beneficial
effect on the healing process of the vagina after POP surgery. It is easy to
administer, cheap, and easy to obtain. Based on research performed in our
institute, is has been shown that vaginal oestrogen in low dosages is very
efficient: in women with vaginal atrophy the vaginal wall thickness doubles
after 6 weeks of use. There is also evidence that oestrogen improves wound
healing, by reducing the inflammatory responses and promoting angiogenesis. If
peri-operative oestrogen therapy would reduce the risk on recurrence by 2%,
this intervention would be cost-effective. Based on our own research, data in
literature, and theoretical background, the reduction in recurrent POP surgery
is expected to be 15% or more. This would mean a cost-saving of 5.1 million
euros per year in the Netherlands.

Primary Objective: This study aims to comprehensively compare the effectiveness
and costs of perioperative topical oestrogen for postmenopausal women
undergoing POP surgery. In this trial, the perioperative use of oestrogen is
considered superior to placebo which results in cost reduction.

Secondary Objective(s): Other aims are to investigate adverse effects and
reasons for the discontinuation of treatment.

This study will be a multicentre, double-blind, randomised placebo-controlled
trial. After inclusion, subjects will receive either topical oestrogen
treatment or placebo treatment 4-6 weeks before their POP surgery till 12
months postoperative.

Recruitment of postmenopausal women to the study will take place in a
multicentre setting across the Netherlands. Recruitment will be done by
gynaecologists.

Randomisation:
Subjects will be randomised 1:1 to perioperative treatment with oestrogen and
perioperative treatment with placebo by the method of online block
randomisation with randomly varying block sizes (in Castor).

Blinding:
Study medication will be blinded. All physicians, researchers, research nurses,
outcome assessors and patients will remain blinded to treatment allocation
until the primary analysis is completed.

Intervention group:
The intervention group receives 0,5 mg oestriol cream (1mg/g, topical
administration) 4-6 weeks preoperative till 12 months postoperative. (First 2
weeks 0,5 mg once a day, thereafter 0,5 mg twice per week).

Control group:
The other group receives a placebo cream (equal schedule as intervention
group).

- The subject will apply a vaginal cream 4-6 weeks preoperatively till 12
months postoperatively. Frequeny: first 2 weeks 1x/day, thereafter
2x/week.(Except the first two weeks postoperative)
- Questionnaires at 4 different time points - baseline, 2, 6, and 12 months
postoperative. (4x 30 minutes).
- Perioperative diary on cream application (from beginning till 6 weeks
postoperative).
- Hospital visit 12 months postoperative, including gynaecological examination