Menopause Dr Renee Verkuijl MD (AMS), FRANZCOG, Masters of Reproductive Medicine (UNSW)

Dr Renee Verkuijl Obstetrician and Gynaecologist General Obstetrics General Gynaecology (including colposcopy and laparoscopic procedures) Infertility (including IVF through QFG)

Learning objectives Medical management of menopausal symptoms Risks and benefits of HRT How to communicate risks and benefits to patients

Menopause Latin: meno= menses and pauein = cease Retrospective definition: 12 months of no periods Average in Australia: 51 years (premature menopause < 40 years in 1%) Peri-menopause or menopause transition current terminology (time around the actual cessation of menses)

Menopausal symptoms 85% will experience some symptoms Vasomotor: hot flushes, nights sweats, formication (“ants crawling”) Urogenital: dry vagina, atrophic vaginitis, dyspareunia, local microtrauma, incontinence Physical changes: decreased fitness and flexibility, changes in distribution of body fat, changes in sleep patterns

Menopausal symptoms Loss of elasticity of skin and support tissues: worsening prolapse, loss of breast tissue, wrinkling Emotional and psychological changes: anxiety or depression, insomnia, lack of concentration, poor memory Effects on bone: osteopenia/osteoporosis Other: change of body shape, loss of libido, change in body hair distribution

Menopausal symptoms Dependent on: The amount and rate of oestrogen depletion The collective inherited and acquired propensities to facilitate adjustment to the changes associated with the ageing process The psychological impact of ageing and the individual’s reaction to the emotional implications of this change of life.

Menopause Early transition: smoking, nulliparity, high altitude Tubal ligation has no effect on timing Family history most important

Endocrinology Less oestrogen production due to the sequential loss of competent follicles being finally depleted by the fifth decade of life Oestrone is main oestrogen produced after menopause Androstenedione (from adrenal gland) is also converted to oestrogens in peripheral sites (dependent on body weight and proportion of adipose tissue)

Endocrinology

Endocrinology With time oestradiol levels drop, FSH and LH levels rise Testosterone levels drop Women might still have regular cycles with high FSH levels (and ovulate!)

Hot flush Oestrogen withdrawal affects the central delta-adrenergic system. This causes release of catecholamines and prostaglandins that produce the hot flushes. LH is released coincident to hot flushes, but does not appear to be the cause. Increased rate of skin electrical conductance, increased skin temperature and decreased body core temperature are objective findings.

Hot flush triggers Cigarette smoking Alcohol Caffeine Stress Heat (or change in temperature) Hot spicy foods Exercise (controversial!)

Hot flush Mean duration is 3 minutes and may be associated with sweating and insomnia 20% experience vasomotor symptoms 10 years after onset of menopause 10% have life-long symptoms

Osteoporosis Long term complication of oestrogen deficiency

Life-style planning Diet Exercise Stop smoking Interpersonal relationships Stress relief and relaxation Holistic approach (bio/psycho/social)

Medical Management Hormone Replacement Therapy Alternatives: Progestogens Delta-adrenergic drugs (Clonidine) Gabapentin SSRI (venlafaxine and paroxetine) Phytoestrogens Steroids (DHEA and progesterone creams) Tibolone (Livial) Selective Oestrogen Receptor Modulators (tamoxifen, raloxifene) Herbals (black cohosh, wild yam and others) Bio-identicals

Hormone Replacement Therapy From 1960s- 1990s menopause was seen as a deficiency state Every post-menopausal woman should be on HRT HRT is good for the heart Should be taken indefinitely to preserve bone mass HRT probably prevents dementia

HRT In the 1960s oestrogen only therapy was the norm, but soon it was apparent that this had a risk of endometrial hyperplasia and uterine cancer in women with a uterus Nurses Health Study and HERS showed risks In 2002 Women’s Health Initiative Study (WHI) showed that HRT is associated with risks

HRT and WHI Large randomised controlled trial to investigate effect of HRT on heart disease, hip fracture and cancer. Mean age 63 years Ceased early due to increased risk of breast cancer in combined arm and increased risk of stroke in oestrogen alone arm

WHI - Overall Combined: increased risk of coronary heart disease, Cerebrovascular accidents, pulmonary emboli and breast cancer, decreased risk of bowel cancer and hip fractures Oestrogen alone: increased risk of strokes, decreased risk of hip and spinal fractures

HRT “window of opportunity” Maybe some benefit if HRT is started early enough in the peri-menopause (prior to tissue damage due to ageing) Danish RCT with 1000 peri-menopausal participants show cardiovascular benefit with 10 year follow up (Oct 2012) Results of the Kronos Early Estrogen Prevention Study (KEEPS 2012), has shown that HRT started soon after the menopause appears safe and relieves many menopausal symptoms, as well as improving mood and cardiovascular risk markers (American RCT, 729 participants)

Consensus (North American Menopause Society, the American Society for Reproductive Medicine and the Endocrine Society) Systemic hormone therapy is an acceptable option for relatively young (up to age 59 or within 10 years of menopause) and healthy women who are bothered by moderate to severe menopausal symptoms. Individualisation is key Consideration should be given to the woman’s quality of life priorities as well as her personal risk factors such as age, time since menopause, risk of VTE, heart disease, stroke and breast cancer

Discussion of pros and cons Individualised approach Consider benefits; effect of symptoms on quality of life Consider risks; take good history regarding risk of VTE, breast cancer, osteoporosis, cardiovascular disease and bowel cancer

HRT The lowest dose of hormone therapy should be used for the shortest amount of time Less than 5 years recommended for combined treatment More flexibility with oestrogen alone (? Up to 10 years)

Investigations prior to starting HRT Complete Hx and examination including PAP and mammogram Bone Density on indication TV USS if irregular bleeding or if risk factors for endometrial cancer Re-evaluate in 4-8 weeks, then 6 monthly

Oestrogen administration Bio-identical (oestrone, oestriol, oestradiol) Synthetic (ethinyloestradiol, mestranol) Non-steroidal estrogens (Diethylstilboestrol) Phytoestrogens (Isoflavones, Lignans, Coumestans) Oral, transdermal, vaginal, implants

HRT Oral oestrogen may be more effective in treating symptoms of androgen excess (>SHBG) Transdermal oestrogen may be more useful in women complaining of decreased libido, or women with relative risks for VTE, breast cancer or cardiac disease Oestriol (ovestin) PV has preference over oestradiol (vagifem) in breast cancer survivors

Progestogen Women with a uterus or who had previous endometriosis need endometrium protection by using a minimum of 10-12 days per cycle of a progestogen In the first 12-18 months after menopause should be on cyclical therapy (to prevent break-through bleeding).

1. Progestogens Reduce the number and severity of hot flushes by up to 85% Not recommended in breast cancer survivors with progestogen receptor positive markers Similar list of warnings and contra-indications in product information as with oestrogen. Medroxyprogesterone Acetate (MPA) 10-20mg daily Alternatively depo provera

2. Clonidine Delta-adrenergic drug originally developed to treat hypertension, relieves hot flushes by reducing peripheral vascular reactivity Mean reduction 40% (placebo 30%) S/e: orthostatic hypotension, headaches, fatigue, nausea, constipation, dry mouth Should be avoided in women with significant depression

3. Gabapentin Used in treatment of epilepsy, migraine, tremor and neuropathic pain 50-60% of control of hot flushes (vs 30% placebo) ? Effect on hypothalamus with reduction in calcium currents s/e light headedness, sleepiness and fatigue Should be tapered down

4. SSRI’s Venlafaxine and paroxetine give 60-70% reduction in hot flushes. Venlafaxine is preferred in tamoxifen users s/e mastalgia, decreased sexual desire and functioning (due to increased prolactin levels) In higher doses (clinical depression) can increase hot flushes Need to be slowly titrated down

5. Phytoestrogens So far similar effects as placebo on menopausal symptoms Dietary intake of isoflavones (high in asian diets, beans and peas) Have estrogen-like biological activity Soy products a major source of isoflavones Need more studies to determine risk for osteoporosis, breast cancer, cardiovascular disease

6. Steroids (Androgen Therapy) There is a positive benefit to add back testosterone in some surgically or naturally menopausal women Behavioural intervention also improves sexual function Side effects No known long term safety profile None licensed in Australia

6. Steroids (progesterone cream) Some women report improvement in vasomotor symptoms, but no improvement on bone density Minimal or no effectiveness in trials Not able to protect endometrium

7. Tibolone STEARs – Selective Tissue Estrogenic Activity Regulators (oestrogenic, androgenic and progestogenic properties) Less effective than conventional HRT in reducing hot flushes (Cochrane 2012) Can be used to improve libido (but risk of VTE) Not safe in breast cancer survivors (LIBERATE) Does not need endometrium protection

8. SERM Selective Estrogen Receptor Modulator Raloxifene ineffective in treatment of vasomotor symptoms Can be used as alternative for prevention and management of osteoporosis Tamoxifen can induce hot flushes in pre-menopausal patients

9. Herbals - Black Cohosh May work as a selective oestrogen receptor modulator, but may also exert an antagonistic effect on serotonin receptors Has no proliferative effect on uterine or breast tissue Most extensively studied alternative treatment Significant reduction in vasomotor and psychological symptoms Takes 2-3 weeks to show effect Risk of adverse liver reaction No long-term data

9. Herbals - Wild Yam Minimal or no effectiveness Initial belief was that wild yam could supply the body with progesterone This process is not possible in humans

9. Herbals - other Evening primrose – may be effective for breast tenderness (not for flushes) Cong quai, ginkgo biloba, ginseng, not better than placebo

10. Bio-Identicals Claim to be the same hormones as the body produces “natural HRT” and derived from plants Made from fatty sterols which are found in yam and soy It does alleviate menopausal symptoms No RCT on risks Natural progesterone might not be effective in endometrial protection

Therapeutic alternatives Cardiovascular risk: lifestyle modifications (diet, non-smoking and exercise, BP and cholesterol control) Flushes may be reduced with SSRIs, high dose progestogens, clonidine, gabapentin or herbals Osteoporosis: calcium, exercise and bisphosphonates Urogenital atrophy: vaginal moisturising preparations +/- topical oestrogens

Thank you Questions?