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Menopause and Mood

Women’s health across the lifespan GP symposium, Epworth, June 4 2016

Dr Roisin Worsley, FRACPEndocrinologist,

Jean Hailes at Epworth Freemasons & Alfred Hospital

Menopause

• The final menstrual period

• Perimenopause – the time around the final menstrual period

• Average age of FMP 51• Average onset of

perimenopause 47

Harlow SD, Gass M,et al.. Climacteric : 2012

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CD

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Hormones across the menopause transition

Burger et al Human Reprod Update 2007

One woman’s hormones in the months prior to menopause

‐36 months ‐25 months ‐17 months ‐7 months

Burger et al Menopause 2008

Menopausal symptoms

• 1 in 3 women have severe psychological symptoms

• 1 in 4 have severe physical symptoms

Mishra GD, Kuh D.. BMJ 2012

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Menopausal symptoms

• Vasomotor symptoms (hot flushes and night sweats)

• Vaginal dryness• Sleep disturbance• Headaches• Joint pain• Mood changes

Symptoms can last many years

• For half of women, symptoms vasomotor symptoms last 7 years

• For half of women, vasomotor symptoms persist 4.5 years after the final menstrual period

• Symptoms persist much longer in a substantial number of women

Date of download: 9/16/2015 Copyright © 2015 American Medical Association. All rights reserved.

From: Duration of Menopausal Vasomotor Symptoms Over the Menopause Transition

JAMA Intern Med. 2015;175(4):531-539. doi:10.1001/jamainternmed.2014.8063

Kaplan-Meier Estimates of Total VMS Duration of Frequent VMS by Menopausal Transition Stage at First VMS Report (A) and by Race/Ethnicity (B)A, By menopausal transition stage at first VMS report. B, By race/ethnicity. VMS indicates vasomotor symptoms.Menopausal transition stage at first VMS report is missing for 9 participants. Median duration for each group is calculated as the value on the x-axis corresponding to the intersection of the dashed horizontal line (50%) with the group’s survival curve.

Figure Legend:

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4

020

4060

8010

0P

erce

nt

41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

020

4060

8010

0P

erce

nt

41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Age in years

Mild hot flushes No hot flushes

Mild night sweats No night sweatsModerate‐severe night sweats

Moderate‐severe hot flushes

Prevalence of hot flushes and night sweats in Australian women aged 40-65 years

Gartoulla, Worsley et al, Menopause, 2015

Mood symptoms at menopause

• Women without a history of anxiety are TWICE as likely to develop anxiety in perimenopause and early postmenopause Bromberger et al Menopause 2013

• Women are TWO to FOUR times more likely to feel depressed during the menopause transition Freeman et al Arch Gen Psych 2006; Bromberger et al Obstet Gynecol Clin North Am 2011

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Vasomotor & depressive symptoms

Blumel, 2004

Hunter, 2013

Joffe, 2002

Juang, 2005

Reed, 2009

Opperman, 2012

Brown, 2009

Yen, 2009

Li, 2008

Hunter, 2013

Bosworth, 2001

Avis, 2001

Cohen, 2006

Freeman, 2006

Freeman, 2009

Bromberger, 2010

Reference

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Fig 1 Profiles of psychological symptoms across midlife and according to age relative to menopause.

Gita D Mishra, and Diana Kuh BMJ 2012;344:bmj.e402

©2012 by British Medical Journal Publishing Group

Depressive symptom scores by menopausal status

020

4060

8010

0

Perc

ent

Premenopausal Perimenopausal Post ≤55 y Post >55 yMenopause status

Moderate-severe depressionBDI ≥ 20

Mild depression BDI 14-19

Mean anxiety scores by menopausal status (lower score = more anxious)

17.216.1 15.7

17.6

0

5

10

15

20

25

Premenopausal Perimenopausal Postmenopausal ≤ 55 y Postmenopausal > 55y

Mean An

xiety Score

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Depressive and anxiety symptoms

After taking into account body mass index (kg/m2), carer status, marital status, employment, housing security, history of mental illness, smoking, weekly binge drinking and education level,

Compared to premenopausal women, postmenopausal women ≤ 55:

– More likely to have depression OR 1.7 (95% CI, 1.1-2.7, p

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Psychotropic medication use by menopausal status

0.41.7 1.7

16.5

11.8

4.7

18.1

1.3

3.2

8.4

22.4

1 1

3.9

19.9

0

5

10

15

20

25

Moodstabiliser Antipsychotic Benzodiazepine Antidepressant

Percent

Premenopausal Perimenopausal Post ≤ 55 years Post > 55 years

Menopause and mood

• Mood symptoms improve after the menopause transition but……Freeman et al JAMA Psychiatry 2014

• This can take years• Hormone therapy may improve depression

during perimenopause Worsley, 2012

• But….• Many women are intolerant of

progestins Andreen, 2010

Hormone therapy

• Estrogen the most effective treatment for hot flushes

• Patches, tablets, gel, pessaries• Causes endometrial thickening / increased risk

of endometrial cancer so women with a uterus must also receive a progestin

• Maybe 30% women negative effects progestin (mood) Andreen, 2010

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HT- risks from WHIEstrogen + Progestin Estrogen Only

Breast Cancer ↑a er 2 yearsHR 1.24 (95% CI, 1.01‐1.53) after 5 yrs, remains elevated after stopping

↓Early post‐interventionHR, 0.55 (95% CI, 0.34‐0.89)

Stroke HR 1.37 (1.07‐1.76) HR, 1.35 (1.07‐1.70)

DVT ↑1.87 (1.37‐2.54) ↑1.48 (1.08‐2.07)

CHD ↔ ↔

All cause mortality ↔ ↔

Monash Alfred Psychriatry Reseacrh Centre 

Chlebowski et al, JAMA Oncol 2015; Mason et al JAMA 2013

Date of download: 9/29/2015 Copyright © 2015 American Medical Association. All rights reserved.

From: Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women’s Health Initiative Randomized Trials

JAMA. 2013;310(13):1353-1368. doi:10.1001/jama.2013.278040

Absolute Risks of Health Outcomes by 10-Year Age Groups in the Women’s Health Initiative Hormone Therapy Trials During the Intervention PhaseNone of the age interactions were statistically significant (at the P 

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Change in case number per 1000 women per 5 years of treatment in women aged 50-59

Estrogen + Progestin Estrogen only

All cause mortality ‐5.3 ‐5.0

CHD ‐0.9 ‐3.8

Breast Cancer +6.8(NAMS +8 per 10,000)

‐1.5

Venous thromboembolism +5 +2

Stroke +1.0 +1.2

Fracture ‐4.9 ‐5.9

Cholecystitis (all ages) +9.6 +14.2

T2DM ‐11 ‐11

Colorectal cancer ‐1.2 0

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Taken from Martin et al Menopausal Hormone therapy: benefits and risks. Uptodate July 2015

Antidepressant use in perimenopausaldepression

• Commonly used to treat anxiety, depression, sleep problems, hot flushes

• SNRIs popular (low dose venlafaxine )• Issues – discontinuity problems, blunting,

aggression, problems with tachyphylaxis• Hypertension w venlafaxine• ?fracture risk

Menopause and pre-existing mental illness• Bipolar Disorder

– More depressive symptoms Marsh et al Bipolar Disord 2012– ?Hormone therapy helpful Freeman et al J Clin Psych 2002

• Schizophrenia– ?worse mood/QoL ?improvement w age Seeman, Maturitas 2012

• Depressive Disorders– Recurrence more common Payne et al, J Aff Dis 2002

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Mood and the menstrual cycle

• Many women notice changes in their illnesses/symptoms with the menstrual cycle

• Changes in mood can also occur– Premenstrual Syndrome– Premenstrual Dysphoric Disorder– Premenstrual Exacerbations of Depression/Anxiety

• PMS often worsens in the 40s as women approach menopause

The menstrual cycle

For a 28 day cycle:• Day One – first day of bleeding• Day 14 – ovulation• Follicular phase: Day 1 – Day 14• Luteal Phase: Day 15-28• Premenstrual: 5 days (or more!!) before

bleeding e.g. Day 23-28

Premenstrual syndrome

• Symptoms in the 1-2 weeks before a period that get better after a period

• Around 80% of women notice some symptoms premenstrually – normal!

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More intrusive symptoms• Physical• Emotional & behavioural

Premenstrual syndrome

Fatigue

Irritability

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Bloating

Anxiety

Cravings

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Low mood

Fatigue Irritability Bloating Anxiety/tension Breast tenderness Mood lability DepressionFood cravings Acne

Increased appetite Oversensitivity Swelling Expressed anger Crying easily Feeling of isolation Headache Forgetfulness Gastrointestinal symptoms Poor concentration Hot flashes Heart palpitations Dizziness

Common symptoms of PMS

Mortola, JF, Girton, L, Beck, L, Yen, SS, Diagnosis of premenstrual syndrome by a simple prospective reliable instrument. Obstet Gynecol 1990; 76:302. Reprinted with permission from the American College of Obstetricians and Gynecologists (Obstetrics and Gynecology, 1990; 76:302). FROM UPTODATE

Premenstrual dysphoric disorder

• PMDD diagnosis focuses on mood

• 5-10% women reproductive age

C. Guille et al. / Epilepsy & Behavior 13 (2008) 12–24

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PMDD diagnosis

Five of : • depression, irritability, anxiety, affect

lability• decreased interest, difficulty concentrating,

fatigue, feeling out of control, insomnia, change in appetite, breast tenderness, breast swelling

• interfere with usual activities

PMDD Diagnosis: CYCLICITY

• Symptoms occur in the luteal phase, remit in the first few days of cycle.

• Symptom free in follicular phase.

• Diagnosis requires a 2 month daily DIARY

C. Guille et al. / Epilepsy & Behavior 13 (2008) 12–24

Tests

• No diagnostic testsLook for:• Other illnesses – thyroid• Menopause transition• Other mood disorder• Current medications

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? cause

• Hormonal fluctuations in the menstrual cycle

• Normal hormone levels / Different brain response

• Progesterone metabolite Allopregnanolone

• ↑Inflammatory markers in luteal phase (IL‐4, IL‐10, IFN‐Ύ; affective symptoms correlate w IL‐2, physical symptoms w IL‐4)

Neuropsychopharmacology (2006) 31, 1249–1263. doi:10.1038/sj.npp.1300952; published online 23 November 2005

Physiological ALLO concentrations

100nM/L

5nM/L

pregnancy

menstrual cycle

(0-40 weeks)

Compiled from: Maguire,Psychoneuroendocrinology (2009) 34S, S84—S90 ; Luisi, S. et al. J Clin Endocrinol Metab 2000;85:2429‐2433; Genazzani, A. R. et al. J Clin Endocrinol Metab 1998;83:2099‐2103

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ALLOPREGNANOLONE CONCENTRATION

low luteal high

ALLO in PMDD ? A paradoxical response

Andreen et al, Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAa modulators.  Psychoneuroendocrinology (2009)

IRRITABILITY SCORE

low

high

Neuropsychopharmacology advance online publication 09 September 2015.doi:10.1038/npp.2015.246

Figure 3

Improvement in symptoms by avoiding luteal rise in allopregnanolone by blocking 5 alpha reductase

Neuropsychopharmacology

Treatment - lifestyle

• Diet ?low salt ?low GI ?more carbs• Maintain weight• Sensible alcohol use• Exercise – throughout cycle• Avoid smoking• Stress reduction• Planning

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Treatment - over the counter

• ?calcium• ?Vitex agnus castus (Chasteberry)• ?Other herbs: St John’s Wort

Treatment - medication

• Oral contraceptive pill use continuously (take sugar pills every three months)

• Antidepressants (SSRIs) help brain to better respond to hormonal fluctuations

• Other

The oral contraceptive pill

• Estrogen + progestin• High discontinuation rate due to mood side

effects• Progestins cause worse mood in some

women

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Progestin in the OCP & anxiety disorders

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11.6 11.8

21.4

35.5

Levonorgestrel Cyproterone Other Drospirenone

Percent

Anxiety disorder

Depression scores by oestrogen dose

0

1

2

3

4

5

6

7

20mcg 30mcg 35mcg+

Med

ian Be

ck Dep

ression Inventory Score

Ethinyl Estradiol dose in the OCP

Choosing an OCP

• It’s difficult!• Mood SEs with OCP I like:

– Zoely– Qlaira– Valette

• & I avoid Yaz/Yasmin

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Mood symptoms at menopause

• Is it my hormones?• Usually it’s a bit of everything• Often need a combination of therapies:

– Lifestyle measures– Psychological therapies– Hormone therapy– Antidepressants