Sex Hormones, Diuresis, LUTS, nocturia an Enigma in the Menopause? Prof Dr Karel Everaert NOPIA Research Group and INPRG Gent, Belgium

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1 Sex Hormones, Diuresis, LUTS, nocturia an Enigma in the Menopause? Prof Dr Karel Everaert NOPIA Research Group and INPRG Gent, Belgium

2 Conflicts of Interest Personal: P2Solutions (smart textile applications) Institution: Grants, Speaker, Consultant for Allergan, Astellas, Medtronic, Ferring Medtronic OptiLuts Chair Frederik Paulson Chair, Ferring

3 Introduction Enigma in the menopause: Why is effect on LUTS of systemic HST different than vaginal administration? Estrogens and UTI? Estrogens and incontinence, urgency? Estrogens and Nocturia? Worsen/unchanged if systemic, improve if local Worsen/unchanged if systemic, improve if local Improve if systemic, worsen/unchanged if local, mostly little data on nocturia available

4 Introduction N=21 ICS Tokyo 2016

5 DYNAMICS OF URINEPRODUCTION GLOMERULUS CAPSULE of Bowman PROXIMAL TUBULE DISTAL TUBULE LOOP OF HENLÉ Descending loop COLLECTING DUCT Ascending loop Glomerular filtration Renal perfusion Osmotic diuresis: Na Atrial natriuretic peptide Aldosteron Water diuresis Vasopressine

6 Urine production Glomerular filtration Renal perfusion Osmotic diuresis: Natriuresis Atrial natriuretic peptide Renin, Angiotensin, Aldosteron Water diuresis Vasopressine GFR Men have higher GFR then women ANP increases GFR (stimulated by estrog and progest)

7 Urine production Glomerular filtration Renal perfusion Osmotic diuresis: Natriuresis Atrial natriuretic peptide Renin, Aldosteron, ANP Water diuresis Vasopressine RAAS/ANP: - Premenop. women = lower activity RAAS compared to men - Sex hormones also seem to influence the local RAAS in the bladder - ACE inhibitors may be a viable treatment approach for OAB - Progesteron = sodium excretion - Estrogens = sodium reabsorption

8 Urine production Glomerular filtration Renal perfusion Osmotic diuresis: Natriuresis Atrial natriuretic peptide Renin, Aldosteron, ANP Water diuresis Vasopressin Vasopressin - Decreased circadian rhythm arginine vasopressin in women - Women need lower dose of desmopressin - Women are more prone to hyponatremia - Women have a significantly higher mean 24-h urine output - Estrogens increase ADH - Progesteron antagonizes ADH

9 Prevalence (%) Prevalence of Nocturia in a US Community-Based Population Males Females Age Group (years) Coyne KS, et al. BJU Int. 2003;42:

10 Impact LUTS on Quality of life Bother of 502 patiënts with BPH symptoms Fear for cancer Disturbed sleep Strong bother Moderate bother Bother Schaamte Frustration Impact on job Impact op social activities Impact relations 0% 40% BPH = Benigne prostaathypertrofie. LUTS = Lower Urinary Tract Symptom Emberton M et al. Int J Clin Pract 2008;62:18-26

11 Most frequent cause of sleepfragmentation Middelkoop et al. J Gerontol A Biol Sci Med Sci 1996;51:M108 M115 Most frequent cause sleepfragmentation in 1485 adults >50 y Nocturia Men Women unknown Fear Problems other 0% 80%

12 One of the most disturbing of all LUTS Bother increases with increasing nocturia episodes 90% 50% Non problematic Problematic 0% >4 N nocturia episodes in 1214 women LUTS = Lower Urinary Tract Symptom Fiske J et al. Neurourol Urodyn 23: , 2004

13 Sleep Deprivation in Humans Increases Urine Production 24 hrs sleep deprivation vs normal sleep with H 2 0 and Na intake controlled (Kamperis et al, Am J Physiol Renal Physiol 2010; 299: F404-11)

14 How innocent is nocturia? - both sleep duration and sleep quality are linked to metabolic health - reduced sleep depth/sleep-related breathing disorders associated with metabolic sy - more metabolic sy in shift work (many studies, countries, jobs) - increased likelihood of obesity (BMI >30 kg/m2) in short sleepers ( 5 h per night) compared with regular sleepers (OR 1,55; n= ; meta-analysis) - independent and strong association between short sleep duration (< 5 h/night) and diabetes type 2 (OR 1,28) - cross-sectional: self-reported short sleep duration (<5 h per night) associated with increased likelihood of hypertension (OR 1,19; n = ) - decrease in OR for diagnosis of hypercholesterolaemia in early adulthood (OR 0,87) M Schmid, Lancet 2014

15 Nakagawa et al. J Urol 2009;181(Suppl):8 How innocent is nocturia? Nocturia 2 associated with mortality in elderly (ajusted for age, gender, comorbidity and drugs) 100% Nocturia 1 Survival HR 2.68 ( ) p< Nocturia 2 90% 0 40 Follow-up (months)

16 CONCOMITANT MEDICATION Causalities of nocturia Intake (water, proteins, sodium, obesity ) Uro-gynecogical (OAB, BOO, neurogenic bladder ) Cardiovascular (blood pressure, metabolic syndrome, physical activity ) NOCTURIA Causative factors Nephrological (water diuresis, salt diuresis, hypercalciuria, nephrogenic diabetes insipidus ) CONCOMITANT MEDICATION Sleep (OSAS, RLS, sleep disruption and shortage, low dopamine diseases ) Hormonal (sex hormones, Diabetus insipidus, mellitus )

17 Treatment Diagnose CARDIOLOGIST GERIATRICIAN CONCOMITANT MEDICATION General Practitioner Real-life Health Care Path of Nocturia Intake (water, proteins, sodium, obesity ) Uro-gynecogical (OAB, BOO, neurogenic bladder ) Cardiovascular (blood pressure, metabolic syndrome, physical activity ) NOCTURIA Causative factors Nephrological (water diuresis, salt diuresis, hypercalciuria, nephrogenic diabetes insipidus ) CONCOMITANT MEDICATION NEPHROLOGIST UROLOGIST Diagnose Treatment Sleep (OSAS, RLS, sleep disruption and shortage, low dopamine diseases ) Hormonal (sex hormones, Diabetus insipidus, mellitus ) General Practitioner

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19 Nocturnal polyuria or not: NPi33 Defined as production of an abnormally large volume of urine during sleep 2 Polyuria (polydipsia) > 40ml/kg/day Exclude polyuria patients (defined as 24h diuresis of >40ml/kg)! Young (aged years) 20% of daily total output Elderly (aged 60 years) 33% of total daily output 1. Weiss JP et al. J Urol. 2011;186: ; 2. van Kerrebroeck P et al. Neurourol Urodyn. 2002;21:

20 Reduced functional bladder capacity - Prostate, prolapse, OAB, neurogenic - No available and validated defined cut-off for a normal, reduced or enlarged bladder - Nocturnal bladder capacity index (NBCi): = actual predicted number of voids (= nocturnal urine production / max observed capacity - 1) RFBC if NBCi > 1.3

21 The TANGO Short Form Screening Questionnaire

22 Figure 6. Current knowledge concerning behavioral and medical therapies available to treat nocturia Intake Uro- Gynecological Cardiovascular Causative factors Nephrological Desmo- pressin CPAP LoE Ia Sleep Hormonal Alfa blockers Furosemide Antimuscarinics LoE Ib Evidences obtained from: - meta-analysis or randomised trials: Level of Evidence (LoE) References: - (23) - (50) - (51) - Expert opinion from ICI-RS NTT To be confirmed by future research. Fluid intake Sleep medication/melatonin Lose weight Salt Diet Physical activity LoE II LoE III Reduce edema Decrease nocturnal blood pressure Pramipexol (increase dopamine) Hormonal substitution LoE IV

23 The perfect desmopressin patient Bothersome nocturia twice or more, nocturnal polyuria, young and healthy

24 Treatment Diagnose CARDIOLOGIST GERIATRICIAN CONCOMITANT MEDICATION General Practitioner Real-life Health Care Path of Nocturia Intake (water, proteins, sodium, obesity ) Uro-gynecogical (OAB, BOO, neurogenic bladder ) Cardiovascular (blood pressure, metabolic syndrome, physical activity ) NOCTURIA Causative factors Nephrological (water diuresis, salt diuresis, hypercalciuria, nephrogenic diabetes insipidus ) CONCOMITANT MEDICATION NEPHROLOGIST UROLOGIST Diagnose Treatment Sleep (OSAS, RLS, sleep disruption and shortage, low dopamine diseases ) Hormonal (sex hormones, Diabetus insipidus, mellitus ) General Practitioner

25 Treatment Diagnose CARDIOLOGIST GERIATRICIAN CONCOMITANT MEDICATION General Practitioner Real-life Health Care Path of Nocturia Intake (water, proteins, sodium, obesity ) Uro-gynecogical (OAB, BOO, neurogenic bladder ) Cardiovascular (blood pressure, metabolic syndrome, physical activity ) NOCTURIA Causative factors Nephrological (water diuresis, salt diuresis, hypercalciuria, nephrogenic diabetes insipidus ) CONCOMITANT MEDICATION NEPHROLOGIST UROLOGIST Diagnose Treatment Sleep (OSAS, RLS, sleep disruption and shortage, low dopamine diseases ) Hormonal (sex hormones, Diabetus insipidus, mellitus ) General Practitioner

26 Treatment Diagnose CARDIOLOGIST GERIATRICIAN CONCOMITANT MEDICATION General Practitioner Real-life Health Care Path of Nocturia Intake (water, proteins, sodium, obesity ) Uro-gynecogical (OAB, BOO, neurogenic bladder ) Cardiovascular (blood pressure, metabolic syndrome, physical activity ) NOCTURIA Causative factors Nephrological (water diuresis, salt diuresis, hypercalciuria, nephrogenic diabetes insipidus ) CONCOMITANT MEDICATION NEPHROLOGIST UROLOGIST Diagnose Treatment Sleep (OSAS, RLS, sleep disruption and shortage, low dopamine diseases ) Hormonal (sex hormones, Diabetus insipidus, mellitus ) General Practitioner

27 Treatment Diagnose CARDIOLOGIST GERIATRICIAN CONCOMITANT MEDICATION Menopause is perfect candidate for desmopressin General Practitioner Intake (water, proteins, sodium, obesity ) Uro-gynecogical (OAB, BOO, neurogenic bladder ) Cardiovascular (blood pressure, metabolic syndrome, physical activity ) NOCTURIA Causative factors Nephrological (water diuresis, salt diuresis, hypercalciuria, nephrogenic diabetes insipidus ) CONCOMITANT MEDICATION NEPHROLOGIST UROLOGIST Diagnose Treatment Sleep (OSAS, RLS, sleep disruption and shortage, low dopamine diseases ) Hormonal (sex hormones, Diabetus insipidus, mellitus ) General Practitioner

28 Low dose, gender specific (Nocdurna 25-50mcgr) Baseline serum sodium > 135 Clearance of BNP normal FU sodium day 3-7, 1 month in high risk Patients (above 65, edema,.) HR of 17 times higher risk for hyponatremia when low baseline sodium in women HR of 3-7 times higher risk for age, GFR and dose Juul K, Accepted BJU 2016

29 The perfect desmopressin patient The best patient has nocturnal polyuria and a bit of a small bladder, a little BPH, some hormonal deficiency or excess of intake,.. We avoid or are careful if: important leg edema, heart/kidney/liver failure, OSAS, Pure retention and OAB patients, polydipsia, frail elderly, low baseline sodium

30 Conclusion Depending on the hormones given and the way of administration, the effect on the symptoms is at first sight contradictory but likely to be depending on the exact cause of the symptom, the hormone given and its way of administration. Nocturia is bothersome and linked to morbidity and mortality Diagnose nocturia with a bladder diary and TANGO, treat causalities Desmopressin and CPAP have level 1a evidence, use low dose and gender specific formulation of desmopressin