1. Dr Jacqueline Guest Consultant Obstetrician and Gynaecologist
THE MENOPAUSE AND HRT
Dr Jacqueline Guest Consultant Obstetrician and Gynaecologist

2. Learning Objectives Physiology of the Menopause and Climacteric
Role of Hormones in the Menstrual Cycle
Symptoms of the Climacteric
Hormone Replacement Therapy (HRT)
Alternatives to HRT

3. Definition of the Menopause
The menopause is the last menstrual period (LMP).
The perimenopause or climacteric is the phase encompassing the menopause.
The climacteric lasts for about two years, but may last for 10 years or longer.

4. Reproductive hormone feedback systems
GnRH
LH FSH
Progesterone Oestrogen

5. The Role of Hormones in The Menstrual Cycle
Gonadotrophin hormones stimulate the ovaries:
follicle stimulating hormone (FSH)
luteinising hormone (LH)
At the menopause ovaries run out of oocytes and they become resistant to the gonadotrophin hormones
Levels of FSH and LH increase throughout the latter stages of the Climacteric and reach a peak 2 to 3 years after the menopause
A level of FSH of more than 30IU/L on 2 separate occasions indicates Ovarian Failure

6. The Role of Hormones in The Menstrual Cycle
There are 3 important oestrogens in women: oestradiol,oestriol & oestrone
Oestradiol is predominant in premenopausal women: produced by the ovaries.
Oestrone is predominant in postmenopausal women : produced by peripheral conversion of androgens in the adipose tissue.
E1 is less biologically active than E2.

7. The Menopause - Acute Symptoms
Hot flushes
Night sweats
Headaches
Panic attacks
Mood swings
Indecisiveness
Insomnia leading to:
irritability
poor short term memory
difficulty with concentration

8. MEDIUM TERM SYMPTOMS Vaginal dryness Dyspareunia Reduced libido
Thinning skin/ hair
Skin formication
Urethral syndrome (frequency, nocturia and urge incontinence)

9. LONG TERM SYMPTOMS CARDIOVASCULAR DISEASE OSTEOPOROSIS
CEREBROVASCULAR DISEASE

10. Rise in female life expectancy over the last 100 years

11. Symptoms of the Climacteric
age range
PRE PERI POST
1 yr
Last menstrual
period

12. Average duration of climacteric symptoms

13. Symptoms of the Menopause
At least 60% of women have hot flushes and night sweats as their main symptom

14. Hormone Replacement Therapy (HRT)

15. OESTROGENS oestradiol oestradiol valerate conjugated equine oestrogens
oestriol
These should not be confused with the oestrogens used in the COC. They are used at a dose which is effectively 1/6th of the dose used in the COC.

16. PROGESTOGENS dydrogesterone norethisterone
19 NORTESTOSTERONE
DERIVATIVES
norethisterone
levonorgestrel
norgestrel
17 HYDROXY-PROGESTERONE DERIVATIVES
dydrogesterone
medroxy progesterone acetate

17. Prescription of HRT: ROUTES
Transdermal: patch or gel
Oral
Intra-uterine (Mirena)
Subcutaneous(implant)
Intra-vaginal (tablets, ring or cream)
Intramuscular (depot)

18. Preparations of HRT Oestrogen Only HRT (tablet, patch, gel, implant)
Sequential Combined HRT - oestrogen and progestogens (tablets or patch)
Continuous Combined HRT - oestrogen and progestogens (tablets or patch)

19. Oestrogen Only HRT
Only to be used in women who have had a total hysterectomy
If the hysterectomy was subtotal, then may need to use progestogens as well (some endometrium may be left behind)
If the hysterectomy was for endometriosis, then progestogens continuously along with oestrogen should be used at least initially

20. Sequential Combined HRT
Sequential oestrogen and progestogen
The addition of the progestogen protects the endometrium and leads to a regular bleed
Single named product available as patch or tablet but individualisation possible eg gel and IUS
Oestrogen for 28 days
Progestogen for 14 days

21. Continuous Combined HRT
Continuous Combined HRT (CCT)
This should not be started until 1 year after the LMP or aged 54. Should also be used after 2 years of cyclical therapy if under the age of 54.
No monthly bleed
Oestrogen combined with progestogen for 28 days

22. Continuous Combined HRT
This preparation leads to no bleeding after the first 6 months of use
Single named product available as tablets or patches
Any oestrogen continuously + any progestogen continuously
The Mirena is now licensed for use with Oestrogen only HRT for 4 years. The advantage is that it can be used in younger women to induce a no-bleed regime.

23. Tibolone or Livial This is an alternative CC HRT
It is a gonadomimetic containing oestrogen, progestogens and androgens
Licensed for vasomotor symptoms and osteoporosis
The risk:benefit ratio similar to HRT in women under 60, but over 60 increased risk of stroke
Slightly increased risk for endometrial cancer
Less risk of breast cancer compared with CCT but increased over E2 only HRT
May help libido due to androgen content

24. How long with sequential HRT?
There are now several papers * that show that prolonged use of sequential HRT can increase the risk of endometrial cancer
Relative risk of endometrial cancer rose from 1.3 to 2.9 for 5 years use
For CCT HRT relative risk fell to 0.2
*Beresford et al. Lancet 1997.
Wiederpass et al. J. of the National Cancer Institute 1999.

25. The advice is therefore
Do not keep women on cyclical therapies longer than 5 years
If the woman is over 54 or her periods have stopped for a year at any age start with CCT
Under the age of 54 continue on cyclical therapy for 2 years and then change to CCT

26. Local oestrogen preparations
For women with vaginal and bladder symptoms who do not need systemic HRT local oestrogens can be used
Vaginal creams and tablets are available
There has been some concern that long term use without progestogens may cause endometrial hyperplasia or cancer

27. Long term treatment of atrophic vaginitis with low-dose oestradiol vaginal tablets*
Women treated with twice weekly Vagifem tablets had an atrophic endometrium after 2 years
Licensed for long term use as required
*L.Mettler and P.G.Olsen
Maturitas.14(1991) 23-31

28. MANAGEMENT OF HRT Initial visit 3 months 6 months
Yearly: BP, breast examination and vaginal examination (3 yearly smears to age 60 and 3 yearly mammography aged 50-64)
Invite earlier visit for specific problems

29. July 2002

33. Risks and benefits www.mhra.gov.uk Vol 1. Issue 2. September 2007
HRT
Risks and benefits
Vol 1. Issue 2. September 2007

34. Benefits of HRT

35. Benefits and HRT: Menopausal Symptoms
HRT effectively relieves vasomotor symptoms
In most cases, 2-3 years therapy is sufficient, but some women may need longer
Symptoms may recur for a short time after stopping it.

36. Benefits and HRT: Coronary Heart Disease
Re-analysis of WHI study suggests a cardio-protective effect if HRT taken in the early menopausal years
No increased risk of CHD has been identified to date with oestrogen-only HRT
RCT’s have shown an increased risk of CHD in women who started combined HRT more than 10 years after the menopause.

37. Healthcare professionals should assess carefully every woman’s risk of CHD before prescribing HRT, irrespective of her age or time since menopause

38. Benefits and HRT: Colorectal Cancer
HRT reduces the risk of colorectal cancer
This is likely to be the anti-oxidant effect of oestrogen

39. Benefits and HRT: Osteoporosis
“osteoporosis is a skeletal disorder characterised by compromised bone strength predisposing to an increased risk of fracture”

40. Schematic representation of lifetime changes in bone mass
Attainment of Consolidation Age related
peak bone mass bone loss
Climacteric

41. RISK FACTORS FOR OSTEOPOROSIS
MINOR
Cigarette smoking
Sedentary lifestyle
Low Calcium intake
MODERATE
FH of osteoporosis
Underweight
High C2H5OH consumption
MAJOR
Early menopause
Prolonged steroid therapy
Prolonged amenorrhoea

42. Management of patients at risk from osteoporosis
Early diagnosis and treatment critical
Bone density screening
Recommend lifestyle factors for self help

43. Benefits and HRT: Osteoporosis
HRT is effective for the prevention of osteoporosis but its beneficial effect on bone diminishes soon after stopping treatment
Because of the risks associated with long term use of HRT, it should only be used for prevention in women who are unable to use other medicines that are authorised for this purpose
However HRT remains the treatment of choice in women with premature ovarian failure

44. Bone mineral content as a function of time and treatment in women soon after the menopause (Christiansen et al. Lancet 1981)
Treatment group
% bone mineral content
Placebo group
months

45. Interventions for prevention and treatment of osteoporosis
Spine
Hip
Bisphosphonates
Etidronate A B
Alendronate
Risendronate
Ibandronate ND
Calcium and Vitamin D
Calcium
Calcitrol
Calcitonin
Oestrogen
Raloxifene
Strontium ranelate
Parathyroid hormone peptides
A: Evidence from RCT ‘s or well designed controlled trial
B: Evidence from other well designed trial (CCT or comparative)
ND: not demonstrated

46. Risks and HRT: Stroke
In RCT’s HRT increased the risk of stroke (mostly ischaemic) compared with placebo
Older women have a greater absolute risk of stroke
Risk may depend on oestrogen dose

47. Risks and HRT: Stroke

48. Risks and HRT: Venous Thromboembolism
Oral HRT has been associated with an increased risk of DVT and PE in RCT’s and observational studies.
Evidence suggests that it is higher with combined HRT than oestrogen-only HRT and that these events are more likely in the first year of use
One study suggests that risk may be lower with a non-oral route

49. Risks and HRT: VTE

50. Risks and HRT: Endometrial Cancer
In women with a uterus, use of oestrogen-only HRT substantially increases the risk of endometrial hyperplasia and cancer in a way that depends on dose and duration
Addition of progestogen cyclically for at least 10 days per 28 day cycle reduces the risk and progestogen continuously eliminates risk

51. Risks and HRT: Endometrial Ca

52. Risks and HRT: Ovarian Cancer
Observational studies suggest that long-term use of all HRT’s may be associated with a small increased risk of ovarian cancer which returns to baseline a few years after stopping it.

53. Risks and HRT: Ovarian Ca

54. Risks and HRT: Breast Cancer

55. Risks and HRT: Breast Cancer
The risk is increased in women who take HRT for several years
Combined HRT has the highest risk
For oestrogen-only HRT the risk is lower
Some studies have not shown an increase for oestrogen-only HRT
Risk increases with duration of use and returns to baseline within a few years of stopping treatment

56. Standard HRT increases breast density in up to 50% of women which may adversely affect radiological detection of Br CA. TIBOLONE increases it by only 5%.

57. Risks and HRT: Breast Ca

58. Are there any alternatives to HRT?
SERMS
Specific
Estrogen
Receptors
Modulators

59. THE IDEAL ‘SERM’ WOULD:
Give oestrogen agonism where it is needed
ie. skeleton, CVS and CNS
Give oestrogen antagonism where it is needed ie. breast and uterus

60. TAMOXIFEN BONE probably favourable but no large trials
CVS favorable effect on lipids but no effect on mortality
UTERUS increase risk of endometrial proliferation, endometrial polyps and Ca body

61. RALOXIFENE
Approved for the prevention of non-traumatic vertebral fractures in post menopausal women at increased risk of osteoporosis

62. Summary of Raloxifene Prevents bone loss
Favourable effect on lipid mechanism
Minor side effects
VTE risk similar to HRT
No endometrial stimulation
No increase in breast or endometrial cancer risk
BUT
Does not help menopausal symptoms

63. Alternatives to HRT: PHYTOESTROGENS
Phytoestrogens are plant substances that have effects similar to oestrogen
ISOFLAVONES
red clover
soy beans
soy products
legumes
LIGNANS
whole cereals
oilseeds
cereals
berries

64. Where isoflavones are an integral part of the diet, menopausal symptoms, CHD, osteoporosis, cancers of breast, colon, endometrium and ovary are significantly lower
The isoflavone red clover is the only alternative treatment to have some trial evidence of benefit for menopausal symptoms

65. Annual Breast Cancer Rates*
19-20/100, /100,000
*Similar patterns also for colon, endometrial and prostate CA

66. Other alternatives Herbalism: eg. Black cohosh, ginseng Homeopathy
DHEA
Acupuncture, magnets
None of these have definitively proven to be of benefit and drug interactions can occur
Read more:

67. Premature Ovarian Failure (Dysfunction)
Cessation of menses before the age of 45
Definition varies with the reference population (2SD below mean)
Affects 1% women under 40
Primary and secondary causes

68. Premature Ovarian Dysfunction
Primary due to chromosome abnormalities eg Turner’s (XO); autoimmune disorders; enzyme defects
Secondary due to chemotherapy, radiotherapy, surgery
Spontaneous ovulation may occur with pregnancy rates up to 5-10%

69. Premature Ovarian Dysfunction
Hormone replacement required to keep tissues healthy including bones and heart
HRT (higher doses) or COCP to age 52
Testosterone as patch or implant
Risks are none use of HRT rather than use at this age. On HRT same risk as age equivalent population for breast Ca, VTE etc