Influence of Nebivolol on Postmenopausal Women
Influence of Nebivolol on Postmenopausal Women
After menopause the coronary artery disease (CAD) risk increases rapidly to an equivalent
 risk of men with the same age. The rising incidence of CAD could be a subsequent decline of
 endogenous estrogen blood levels after the menopause. Estrogen leads to vasodilation and
 vasoprotection through an increase of Nitric Oxide (NO). NO deficiency results in endothelial
 stiffness and dysfunction with a subsequent initiation of atherosclerosis. Menopausal status
 is associated with an increase of the sympathetic nerve activity leading to hypertension,
 increased heart rate and palpitations. Recent studies show an importance of vasoactive
 substances (e.g. NO) in the physiology of hot flashes. Thus, hot flashes may be associated
 with a decreased NO production and release. Additionally, it is well known that during and
 after menopause women experience a change in sexual function (declined libido and increased
 dyspareunia) due to decreasing estrogen blood levels. Recently, a new angiostatic parameter -
 Endostatin (ENST) - has been shown to be involved in EC function. There is also evidence that
 ENST levels increase during NO stimulation. Nebivolol, a ß-blocker of the third generation,
 has been shown to release NO to a significant amount in the EC. It is safe and effective in
 reducing blood pressure to the target level. However, there is no data of the effect of
 Nebivolol on sexual function, on clinical symptoms (palpitations, increased heart rate and
 hot flashes) and ENST in postmenopausal women. The present study investigates the effect of a
 NO-releasing ß-blocker compared to a phytoestrogen therapy considering clinical signs of
 menopause such as palpitations, hot flashes and sexual functioning in postmenopausal women.
 Therefore, the use of a ß-blocker treatment is warranted. Further, this study tries to
 elucidate the role of NO release in postmenopausal symptoms and may gain new insights in the
 pathophysiology of hot flashes and increased sympathetic nerve activity. Thus, this trial
 should explore an advantage of Nebivolol therapy in contrast to a phytoestrogen therapy.

 Null hypothesis: Climacteric disorders as measured by the MRS-II in patients with a Nebivolol
 therapy is not lower than in patients with phytoestrogen therapy. Alternative hypothesis:
 Climacteric disorders in patients as measured by the MRS-II with a Nebivolol therapy is lower
 than in patients with phytoestrogen therapy.
1. Background

 CAD is the leading cause of mortality for women in US as well as in Austria and most
 developed countries.

 Major risk factors are hypertension, diabetes and the postmenopausal status. After the
 menopause the CAD risk increases rapidly to an equivalent risk of men with the same age.

 In all ethnic groups, hypertension is more prevalent among women than men after the age
 of 59. Over 75 years 75,2 % of females and 63,7% of males perform a hypertensive
 vascular status.

 Menopausal status is associated with a decline of endogenous estrogen levels resulting
 in a manifest estrogen deficiency. This estrogen decline is also associated with a
 subsequent increased risk for CAD.

 The main effect of estrogen is a vasodilatation and an anti-atherosclerotic action
 through different mechanisms.

 Recent studies are describing that the estrogen deficiency and the subsequently NO
 deficiency results in a disordered endothelial function and a permanent
 vasoconstriction, that is one of the major reasons for postmenopausal hypertension and
 CAD.

 Clinical symptoms of postmenopausal women:

 - Palpitations and tachycardia Postmenopausal women complain about heart palpitations,
 throbbing and subjective sensed high heart rate and tachycardia, which can be explained
 by a sympathetic over activity in postmenopausal women.

 This clinical symptoms are associated with a significant decrease in quality of life and
 well- being in postmenopausal women.

 - Hot flashes Hot flashes are the most common symptom and occur in most postmenopausal
 women (75%). Hot flashes are experienced as a feeling of intense heat with sweating and
 rapid heartbeat. The typical duration is between two and thirty minutes. Risk factors
 for hot flashes are - equal to CVD - high body mass index and smoking.

 Furthermore, it can be supposed that the NO decrease in postmenopausal women is
 responsible for the hot flashes.

 - Sexuality Sexuality is an important quality-of-life issue, also in elderly. Therefore,
 sexual dysfunction is considered a serious quality-of-life-related health problem.
 Furthermore increasing dyspareunia and decreasing libido and responsivity correlated
 with decreasing estrogen levels.

 - Endostatin (ENST) ENST, a 20-kDa C-terminal fragment cleaved from type XVIII collagen,
 is a naturally occurring protein that blocks the formation of blood vessels, inhibits EC
 proliferation, migration and angiogenesis. Furthermore, there is evidence that ENST
 induces an acute NO release and finally leads to vasodilation and therefore works
 against endothelial dysfunction.

 However, since there is no data on ENST serum levels in postmenopausal women as well of
 the effect of Nebivolol on ENST serum levels, we will investigate baseline ENST levels
 and after 3 month of treatment compared to patients treated with phytohormones.

 - Nebivolol Nebivolol, a ß-blocker of the third generation, has been shown to lower
 blood pressure with great safety and efficacy in men as well in women and was well
 tolerated.

 Beneath its specific beta-1-receptor blockade Nebivolol has a NO-releasing effect
 through a ß3-receptor-agonism. Nebivolol combines a potent ß1-adrenoreceptor-blocking
 activity (mostly ascribed to its D-enantiomer) with additional vasodilating properties
 (attributed to its L-enantiomer and also D-enantiomer).

 Nebivolol causes a vasodilatation of the vessels and reduces the progress of
 atherosclerosis which is a main risk factor for CVD and hypertension.

 The current general guidelines for hypertension recommend treatment with a Thiazide
 Diuretic as a first line medication in hypertension. In contrary to Diuretics and
 ACE-blockers - ß-blockers also reduce the heart rate and have positive antagonistic
 influence on the sympathetic nerve system. The augmentation of the heart rate during the
 menopause is sensed as a very unpleasant and unbearable situation for most of the
 postmenopausal women. Thus, the increase in sympathetic nerve activity and clinical
 symptoms of palpitations or increased heart rate warrant the use of a ß-blocker for the
 treatment in our cohort.

 Additionally, we hypothesise, that through an improvement of the endothelial function
 with Nebivolol the number of hot flashes in postmenopausal women can be reduced.

 Recent studies have shown positive effects on the erectile dysfunction in men during
 treatment with Nebivolol. As the physiologic and embryologic conditions are almost
 similar in men and women, so we expect similar improving effects on the sexual
 dysfunction in our female study group.

 Therefore, we want to investigate the effect of Nebivolol on blood pressure, heart rate,
 hot flashes, sexual function, ENST, testosterone levels in postmenopausal women with
 menopausal disorders.

 1.2 Rationale of the study

 We want to investigate the effect of Nebivolol in comparison to a phytoestrogen therapy
 on climacteric disorders as measured by the Menopausal rating scale II (MRS-II). In
 addition we will investigate the following:

 - the heart rate

 - the number of palpitations

 - the number of hot flushes

 - the sexual function

 - the blood pressure

 - the serum level of Endostatin

 -  the serum level of Testosterone in postmenopausal women.

 2 METHODS 2.1 Measurement of the blood pressure Measurement of the blood pressure
 according to Riva Rocci will be performed at the beginning and after 12 weeks (end
 of the study). Measurements will be taken in sitting position after five minutes
 rest. Three consecutive measurements will be taken and the average of these
 measurements will be recorded.

 2.2 ECG A 12-lead ECG will be written to rule out AV-block and bradycardia (<50/min).

 2.3 Blood parameters

 Prestudy screening:

 - FSH

 - TSH

 - testosterone

 - estrogen

 - DHEA

 -  SHBG

 -  prolactin

 -  BNP

 -  hsCRP

 -  liver parameters

 -  kidney parameters

 -  electrolytes

 -  blood glucose

 Our patients have to show a blood level of estrogen <20pg/ml and FSH >35 mIU/ml to
 verify the status of menopause.

 To rule out another endocrine cause of a possible sexual function alteration we check
 the blood levels of TSH, Prolactin, DHEA (Dehydroepiandrosterone) and SHBG (Sex Hormon
 Binding Globulin).

 2.4 Analysis of Endostatin Within the routine blood analysis we will also detect the
 blood level of ENST.

 The RD191076100 Human Endostatin ELISA is a sandwich enzyme immunoassay for the
 quantitative measurement of endostatin protein in human serum.

 2.5 Female Sexual Function Index We will use the German version of the female sexual
 function index (FSFI-D) that was validated in 2004. This questionnaire is a proven
 instrument to evaluate the female sexual function especially in (post)menopausal women.

 We will hand out this questionnaire twice: At the beginning and after our study (12
 weeks later). During the completion of the questionnaire by the study participant, a
 gynecologist will be attendant to help the women to complete the questionnaire.

 This way we want to analyze if the treatment with Nebivolol has an effect on the sexual
 function of women. We have added the questionnaire to the appendix.

 2.6 Menopausal Rating Scale II We are going to use the Menopause Rating Scale II (MRS
 II). This self-assessment scale to quantify menopausal symptoms includes 11 questions to
 evaluate the "quality of life" in our cohort.

 We will hand out this questionnaire twice: At the beginning and after our study (12
 weeks later). During the completion of the questionnaire by the study participant, a
 gynecologist will be attendant to help the women to complete the questionnaire.

 2.7 Hot flashes/palpitations diary At the beginning of our study, the diary will be
 introduced to the patients by the treating physician. There the number of hot flashes
 and palpitations per day should be written down. The diary contains 12 pages, one page a
 week.

 At the beginning we will perform an anamnesis to get informed about the average number
 of hot flashes and palpitations per day before the medication.
Inclusion Criteria:

 -  Menopausal patients (estrogen <20 pg/ml and FSH >35 mIU/ml)

 -  The patients are sexually active

 -  The patients have hot flushes

 -  The patients have palpitations or extrasystoles

 Exclusion Criteria:

 Contraindications for a beta-blocker therapy such as:

 -  Patients with COPD

 -  Patients with an AV-block

 -  Patients with a bradycardia (meaning a heart rate <50 beats per minute)

 -  Patients with hypotension (RR <100/80 mmHg)

 -  Patients with a PAD (stage III, IV)

 -  Patients with Asthma

 -  Patients with Morbus Raynaud

 -  Patients with a carcinoma

 -  Patients, who have already been treated because of hypertension

 -  Patients, who receive hormone replacement therapy