Dr. Annie Evans MA MFFP Women s Health Specialist Bristol Royal Infirmary Bristol Nuffield Hospital, U.K.

1. Dr. Annie Evans MA MFFP Women’s Health Specialist Bristol Royal Infirmary & Bristol Nuffield Hospital, U.K.

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3. Dr Annie Evans 2007 Overall hormonal contraception useby age Same graph, but distinguishes between Long Term, POPs and COCs. The majority of women are using COCs.Same graph, but distinguishes between Long Term, POPs and COCs. The majority of women are using COCs.

4. Dr Annie Evans 2007 % women experiencing accidental pregnancy in first year of use1 Non-hormonal methods

5. Dr Annie Evans 2007 % women experiencing accidental pregnancy in first year of use1 Hormonal methods

6. Dr Annie Evans 2007 Contraception in the Older Woman ? Fertility ? Fear of pregnancy Fear of “taking hormones” ? TOP rate

7. Dr Annie Evans 2007 ABORTION RATES: 35 to 44 Year Olds The same for women over 35 years old (even more dramatic).The same for women over 35 years old (even more dramatic).

8. Dr Annie Evans 2007 TOPs as a % of pregnancies by age group, E & W, 20001

9. Dr Annie Evans 2007 TOP rates Women > 40 yrs in the UK 2nd highest % of women conceiving ? TOP of any age group ? 40 % conceptions ? TOP

10. Dr Annie Evans 2007 Fertility Rates Age <25 40 45 Fertility 85 45 15 pregnancies per 100 women years At 40 approx 50% women still fertile

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12. Dr Annie Evans 2007 Sexual Health in Middle Youth! Changing social structure : 42% divorce rate Lack of knowledge of STIs and need for condoms use with new partners + check-ups Back out in “the sexual market place”… a scary place to be!!!

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15. Dr Annie Evans 2007 Contraceptive Choices Sources of information Media (health risks / scares) Other women (minor side effects) Medical professionals (rarely) Choices often driven by misinformation FEAR AND ANXIETY

16. Dr Annie Evans 2007 Common Myths Contraception = “the best of a bad lot” Pregnancy “won’t happen to me” Menstrual cycle and bleed = normal and good No bleeding = unnatural and harmful Own hormones all good Other hormones all bad………….

17. Dr Annie Evans 2007 Common Myths So hormonal methods harmful……… the longer they are used and the older you get!!

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19. Dr Annie Evans 2007 The Perimenopausal Years Around 40 ovarian function wanes as frequency of ovulation declines Women at this age need simultaneous contraception and hormonal stabilisation Perimenopause can last at least 10yrs

20. Dr Annie Evans 2007 All in the mind? Often complaints assumed to be psychosomatic : “You’re too young for the change” “It’s just your age” “Women’s hormones are strange” “Normal? What’s normal?”

21. Dr Annie Evans 2007 Perimenopausal symptoms Menstrual problems ? PMS, irritation, paranoia, panic Pre-menstrual and menstrual migraine Insomnia, tiredness Joint aches, flu-like symptoms Poor concentration, verbal memory Loss of libido, loss of drive Inability to multi-task Inability to COPE!!

22. Dr Annie Evans 2007 Menstrual Cycle Changes shortening cycle length erratic cycle length increased/decreased length of bleed spotting and changed type of bleed clots, heavy flow, “tarry” bleeding intermenstrual bleeding unpredictability interferes with life

23. Dr Annie Evans 2007 Premenstrual Syndrome Worsens dramatically with... irritability, aggression, paranoia, emotional lability,panic attacks problems worse premenstrually - expands to take up more and more of cycle

24. Dr Annie Evans 2007 Additional Symptoms Tiredness: overwhelming Insomnia: recurrent wakening, NOT purely related to night sweats Joint aches Cyclical breast tenderness Palpitations Bladder irritability: urethral syndrome

25. Dr Annie Evans 2007 More Symptoms ?Headaches and migraine especially premenstrual / menstrual Night sweats (more than hot flushes) Loss of libido Loss of “drive” Inability to perform several tasks simultaneously

26. Dr Annie Evans 2007 Even More Symptoms... Poor concentration (having to read things several times) Forgetfulness (list making,“going upstairs” driving in wrong direction) Poor verbal memory (names & point of what you are saying!)

27. Dr Annie Evans 2007 Had Enough Symptoms? Declining feelings of self-worth Worsening “depression” “Is this normal?” “Am I going mad?”

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30. Dr Annie Evans 2007 Hormonal Instability Ovarian activity doesn’t decline steadily Some cycles anovulatory Several months of poor ovarian activity, followed by improvement again Total unpredictability!

31. Dr Annie Evans 2007 Hormonal roller-coaster….

32. Dr Annie Evans 2007 Menopausal Transition Accepted theory: “ OVARY is the CONDUCTOR” Born with vast but finite no. follicles Exhaustion of follicular reserve ? Cessation of menstrual cycles ? Infertility

33. Dr Annie Evans 2007 Menopausal Transition Alternative Theory (Wise PM, Kentucky, 1998) “HYPOTHALAMUS ORCHESTRATES MENOPAUSAL TRANSITION” Complex interplay of changes in CNS governs timing of menopause Hypothalamus is pacemaker initiating cascade of events ? menopause

34. Dr Annie Evans 2007 Studies of the Perimenopause Perimenopausal women have the most VARIABILTY in ovarian steroid hormone profiles of any age group BUT mean serum oestrogen levels were no different in this age group from those of younger women Fitzgerald CT et al, Br. J. Obstet Gynae, 1994

35. Dr Annie Evans 2007 Possible Mechanisms Kentucky group suggest that patterns of neurotransmitter activity critical in maintaining patterns of GnRH secretion, become less ordered Daily rhythmicity is affected first First sign is INSOMNIA

36. Dr Annie Evans 2007 Management of Transition Women in the perimenopause are more likely to seek medical advice than their pre- or post-menopausal counterparts McKinlay SM, Maturitas 1992 Variations in FSH, inhibin and oestrogen levels transient - unreliable in diagnosis Need individual longitudinal data : menstrual / symptom diary

37. Dr Annie Evans 2007 Management of Perimenopause Education / Information / Support Simultaneous need for contraception and hormonal support Must stabilise hormonal environment

38. Dr Annie Evans 2007 Migraine in the Perimenopause ? Triggered by falling oestrogen levels in late luteal phase of the cycle Endocrine shifts more pronounced in perimenopause SO premenstrual and menstrual migraine worsens

39. Dr Annie Evans 2007 Migraine in the Perimenopause Also occurs in other situations where there is sudden drop in oestrogen levels PFI on the COC Postpartum - oestrogen levels plummet Used to occur during placebo days of “21 days on / 7days off” HRT

40. Dr Annie Evans 2007 Rx Perimenopausal Symptoms Treatment consists of stabilising E levels during late luteal phase Regular cycles: top-up with natural E:2nd half each cycle transdermal/percutaneous better than oral - produces much more stable level

41. Dr Annie Evans 2007 Why transdermal / percutaneous? Produces stability of hormonal levels Replicates PRE – MENOPAUSAL MILIEU: greater E2-E1 ratio Greater E1-E2 ratio of the postmenopause achieved better with oral oestradiol NOTELOVITZ, M. ed. MATURITAS 2003

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43. Dr Annie Evans 2007 Rx Perimenopausal Symptoms For 2nd half of cycle : (e.g. day 14 – 28) Percutaneous oestradiol : 1 dose Oestrogel / 0.5g Sandrena/day Transdermal oestradiol 25?g patch twice weekly ?Continue day 1 +/- day 5 of next cycle Gels even better than patches!

44. Dr Annie Evans 2007 Rx Perimenopausal Symptoms Irregular cycles : Continuous natural oestrogen (transdermal) at sufficient dose OR own endogenous oestrogen level will break through and create fluctuations ?Cyclical progestogen needed to protect endometrium or IUS better option?

45. Dr Annie Evans 2007 Rx Perimenopausal Symptoms Suppress ovulatory cycle: With high static oestrogen levels Tricycle low dose COC or high dose transdermal oestradiol continuously with cyclical progestogen By reducing the oestrogen level e.g. Danazol, Tamoxifen, GnRH analogues (medical menopause)

46. Dr Annie Evans 2007 Management decisions….. Difference between : evidence-based medicine which allows no individual course of action without large prospective RCTs & experientially-based medicine based on clinical practice & biological plausability!

47. Dr Annie Evans 2007 Traditional Contraceptive Advice ? fertility & less sexually active: natural methods barrier methods IUD or if family complete: sterilisation (male or female)

48. Dr Annie Evans 2007 Pattern of Contraceptive Use Leaves women “at the mercy of their own hormones” Vulnerable to perimenopausal symptomatology

49. Dr Annie Evans 2007 Effects on Oestradiol of Contraceptive Method Depo injection / POP (LNG or NETA) ? may suppress IUS / Etonorgestrel POP or implant maintain within normal range COC suppression, but addition of synthetic E Non-hormonal left with own fluctuating levels

50. Dr Annie Evans 2007 Combined Pill Can be used in non-smoker with no other risk factors for arterial disease Helps control oestrogen-deficiency symptoms Protects bone ? 20µg with newer progestogen Issues include breast cancer, arterial disease and venous thromboembolism Must “pick out risky women”

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55. Dr Annie Evans 2007 LOCAL ACTION LNG released to endometrium unresponsive to oestradiol inactive and atrophic less prostaglandin production LESS DYSMENORRHOEA LIGHTER MENSES

56. Dr Annie Evans 2007 Endometrial concentration

57. Dr Annie Evans 2007 Local vs systemic delivery Plasma [LNG] lower than with COCs or implants1–3 LNG level equivalent to 2 POPs /week4 Endometrial LNG level 1000x > plasma Plasma oestradiol normal for fertile women5

58. Dr Annie Evans 2007 Benefits of local action No significant change in : Blood pressure Serum lipids Coagulation factors Carbohydrate metabolism Liver function

59. Dr Annie Evans 2007 Hormonal side-effects Systemic – rare, most common: skin ? ‘progestogen-sensitive women’ Mainly local – endometrial shedding ? intermittent light bleeding – first 3 months1 Honest counselling ? toleration

60. Dr Annie Evans 2007 Other benefits Ectopic pregnancy rate low: LNG-IUS: 0.02 per 100 woman-years Nova T : 0.25 per 100 woman-years1 Pelvic inflammatory disease rate Lower than for copper IUDs Most marked in under 25s2

61. Dr Annie Evans 2007 Ease of reversal Endometrium returns to normal 30 days after removal and menstruation occurs Easily and completely reversible

62. Dr Annie Evans 2007 Rapid return to fertility Conception rates comparable to no contraception used1,2 Normal menstruation returns within 30 days3 Easily and rapidly reversible1

63. Dr Annie Evans 2007 Effect on menstruation Objective reduction in menstrual loss1 86% in 3 months 97 % in 12 months Gradual reduction in no bleeding days 17% users bleed free at 1 yr 27% at 5yrs 60% by end of 2nd 5 yrs2

64. Dr Annie Evans 2007 Duration of Use Endometrial changes complete within 3 months1 Continue until system renewed Endometrial atrophy persists on renewal

65. Dr Annie Evans 2007 Long-Term Use: Sweden‘99 Assessment of long-term effects by analysis of health parameters eg: bleeding pattern, Hb ,weight, bp Assessment of acceptability & bleeding pattern in women who became menopausal & began HRT with IUS in place

66. Dr Annie Evans 2007 82 women, 12 years1 From European multi-center study 82 women who had 7 yrs use with 1st IUS, offered 2nd No reported pregnancies 77% reported no health problems Bleeding pattern improved over 2nd segment So Hb levels rose

67. Dr Annie Evans 2007 Bleeding pattern in the first 5-year period

68. Dr Annie Evans 2007 Bleeding pattern in the second 5-year period

69. Dr Annie Evans 2007 Women with no bleeding 60% of women bleed free by end of second segment: Either remained bleed-free after 1st IUS, or quickly became so

70. Dr Annie Evans 2007 Bleeding pattern: acceptability Positive benefit of amenorrhea Not only for those with menorrhagia Effect on quality of life1

71. Dr Annie Evans 2007 Continuation rates 1 year post-insertion: 94% 2 years post-insertion: 87% 3 years post-insertion: 82% 4 years post-insertion: 76% 5 years post-insertion: 65%

72. Dr Annie Evans 2007 Sterilisation LNG-IUS Permanency vs Reversibility Cost and morbidity vs Low cost Operation vs Office procedure Menorrhagia? vs Oligo/amenorrhea Hysterectomy? vs Hysterectomy ?? Failure rates ?

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74. Dr Annie Evans 2007 Alternative to hysterectomy RCOG Guidelines (UK): ‘Appropriate medical alternatives must have been discussed and rejected…’

75. Dr Annie Evans 2007 Alternative to hysterectomy 50 women awaiting hysterectomy for menorrhagia – LNG-IUS inserted1 41 ?? bleeding – taken off list 40 ? dysmenorrhea 28 ? PMS

76. Dr Annie Evans 2007 Alternative to hysterectomy

77. Dr Annie Evans 2007 Alternative to hysterectomy No difference in quality of life measures Overall costs 3x higher in hysterectomy group!

78. Dr Annie Evans 2007 Menopausal transition When menopausal symptoms occur: Just add oestrogen!!

79. Dr Annie Evans 2007 Effects of changing hormonal milieu: on genital tract

80. Dr Annie Evans 2007 Pre- menopausal EFFECTPeri- menopausalPost- menopausal Progesterone CYCLlCAL IMMUNOSUPPRESSlON Oestrogen PSYCHO-NEURO- ENDOCRlNE +/- MENORRHAGlA Oestrogen ?? ATROPHY VAGlNlTlS

81. Dr Annie Evans 2007 Progesterone Chlamydia detection Recurrent Candidiasis Oestrogen Recurrent Herpes Recurrent Bacterial Vaginosis Oestrogen ?? Vaginitis Pre- menopausal EFFECTPeri- menopausalPost- menopausal

82. Dr Annie Evans 2007 Cyclical effects Salpingitis Chlamydia Endometritis Bact.Vaginosis Candidiasis Menses Follicular Luteal

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84. Dr Annie Evans 2007 Hormonal MilieuInfection Tubal Damage Vaginal Abnormal Discharge Bleeding

85. Dr Annie Evans 2007 Cyclical effect on Flora Schematic Lactobacilli concentration 4 fold increase 14 28 Menses Follicular Luteal

86. Dr Annie Evans 2007 Cyclical effect on Flora Recovery of Prevotella 56% 28% 1 5 7 12 19 24 Menses Follicular Luteal

87. Dr Annie Evans 2007 [Prevotella] [Lactobacilli] 1 14 28 Menses Follicular Luteal Cyclical effect on Flora

88. Dr Annie Evans 2007 Symptoms 1 14 28 Menses Follicular Luteal Cyclical effect on BV

89. Dr Annie Evans 2007 Symptoms 1 14 28 Menses Follicular Luteal Menorrhagia effect on BV

90. Dr Annie Evans 2007 Question Bleeding? ? BV Vaginal Epithelium

91. Dr Annie Evans 2007 Question Chlamydia IUD Endometrium? Bleeding? ? BV Vaginal Hormonal change Epithelium

92. Dr Annie Evans 2007 Options‘Treat the symptom…’ Metronidazole….ad nauseam? Metr. or Clindamycin cream…etc? Prophylactic Metronidazole ? Lactobacilli (L.crispatus) ? Acidic gel installation ?? Co-amoxyclav

93. Dr Annie Evans 2007 Options‘…or treat the cause’ Reduce or prevent menstruation: Mefenamic acid Tricycle OC + Metronidazole Levonorgestrel IUS (Mirena) Transdermal oestradiol – luteal

94. Dr Annie Evans 2007 Candida or Herpes?

95. Dr Annie Evans 2007 Perimenopause

96. Dr Annie Evans 2007 Premenstrual syndrome worse Increased herpes recurrences Timing: immediate premenstrual Herpes + Perimenopause?

97. Dr Annie Evans 2007 Premenstrual syndrome worse Increased herpes recurrences Timing: immediate premenstrual R Aciclovir suppression (luteal only) Treat perimenopause? Herpes + Perimenopause?

98. Dr Annie Evans 2007 PremenstruallyRecurrent Herpes Reported by perimenopausal women Rx Luteal phase Aciclovir suppression Successful prevention of recurrences 25-50% of drug cost

99. Dr Annie Evans 2007 43y p0+0 (22 y Follow-Up) 1983 Primary infection HSV type 2 83-89 Recurrences & Aciclovir suppression 89-00 Episode-free interval 2000 Premenstrual recurrences each cycle & severe perimenopausal symptoms 9.2001 Rx Aciclovir only in luteal phase 2.2002 Luteal phase Oestrogen + IUS - LNG 3.2005 No recurrence, No PMS etc

100. Dr Annie Evans 2007 Hypothesis Hormonal effect on: brain immunological system Effect of severe stress Effect in luteal phase Premenstrual recurrences

101. Dr Annie Evans 2007 PremenstruallyRecurrent Herpes Reported by perimenopausal women Rx Luteal phase Aciclovir suppression Successful prevention of recurrences 25-50% of drug cost Treat perimenopausal symptoms Rx Luteal phase transdermal estrogen No further recurrences 6 – 36 month follow-up

102. Dr Annie Evans 2007 PremenstruallyRecurrent Herpes Treat the symptom? Luteal – phase Aciclovir Transdermal estrogen +/- LNG IUS

103. In the Perimenopause…. we need MORE THAN JUST CONTRACEPTION!!

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