Dr Khaldoun Khamaiseh FRCOG MRCP Consultant Obstetrician & Gynecologist & Reproductive Endocrinologist

Endocrinology and physiology

Natural history

Symptoms of the menopause

Long term risks

Premature Ovarian failure

From puberty to the menopause menstrual and reproductive function in women is governed by endocrine function of the brain(Hypothalamus and pituitary gland) ovary and uterus

The first endocrinologist was a gynaecologist

The maximum number of eggs (about 7 million) is reached at 20 weeks of gestation and will have already fallen to 1–2 million by birth. Atrition continues throughout life

By puberty , approximately 250,000 follicles remain with the potential for up to 500 ovulations.

Only a few thousand oocytes left as a woman enters her forties

None in the post menopause. It is the depletion of oocytes which eventually leads to the

cessation of menstruation, the cardinal sign of the menopause.

This leads to sharp drop in Estradiol and rise in FSH

The ovary shrinks and the uterus becomes smaller in size

and the vagina becomes atrophic

Menopause is the last menstrual period. The average age at menopause is approximately 51 years. Happens gradually with irregular anovulatory cycle

Peri menopause or climacteric . It is the time period from when the ovaries start to fail until 12 months after the last menstrual period.

Premature menopause is defined as menopause that occurs before the age of 40 years.

Hot flushes

Night sweats

Mood swings

Urogenital atrophy

For some women, menopausal symptoms are mild and of short duration, and do not require management beyond lifestyle adjustments, education, and reassurance.

Osteoporosis

Cardiovascular disease and stroke.

Dementia ?? Directly related to a fall in estrogen levels.

Increase in bodyweight with age, around abdomen tends to begin at or near menopause.

Hormone Replacement Therapy

(HRT)

Types

Routes

Benefits

Side effects

Risks

Estrogen only

Sequential combined regimens

Continuous combined regimens

Tibolone (Livial)

SERM (Raloxifene)

Testosterone

Mirena

Alternatives to HRT

In women with a uterus, oestrogen-only therapy is associated with a significantly increased risk of developing endometrial hyperplasia and cancer.

Used in women who had hysterectomy.

Natural conjugated: Premarin

Synthetic: Estradiol Valerate(Estrofem)

The addition of Progestogen to Estrogen therapy reduces the risk of endometrial disease, but regimens should usually include at least 10 days in each monthly cycle.

age of 54, or her periods have stopped for more than one year at any age.

Tibolone has oestrogenic, progestogenic and androgenic properties.

It appears to be effective in the treatment of vasomotor symptoms.

Recent data suggest that tibolone may also be associated with an increased risk of breast cancer, but less than that associated with combined oestrogen and progestogen preparations.

Reduces the incidence of vertebral fractures in women with osteoporosis.

There is no current evidence of protection against fractures at the hip or at other sites.

Use of raloxifene is associated with reduced risk of breast cancer but :

Increased incidence of vasomotor symptoms.

Vasomotor symptoms : hot flushes. Improvement is usually noted within four weeks. In most cases, 2–3 years’ therapy is sufficient

Mood or sleep disturbances: HRT often improve sleep by alleviating night sweats. .

Urogenital symptoms: vaginal dryness, soreness, Paiful sex, and urinary frequency and urgency respond well to estrogens, which may be given either topically or systemically.

Evidence show that HRT reduces the risk of spine and hip osteoporotic fractures.

HRT is currently not recommended as a first line treatment for osteoporosis prevention.

While alternatives to HRT are available for the prevention and treatment of osteoporosis in elderly women, estrogen may still remain the best option, particularly in younger and/or symptomatic women. It is cheaper than other alternatives such as bisphosphonates.

Results from the estrogen progestogen arm of the WHI study show that HRT reduces the risk of colorectal cancer by about one third. There is no information about HRT in high risk populations, and current data do not allow prevention as a recommendation (BMS Consensus).

Adverse effects account for almost 35% of HRT discontinuations

Tend to occur continuously or randomly through the cycle. They include

Fluid retention

Bloating,

Breast tenderness/enlargement

Nausea, dyspepsia

Headaches and leg cramps:

Tend to occur in a cyclical pattern during the progestogen phase of cyclical HRT.

Fluid retention

Acne

Breast tenderness

Headaches/migraine

Mood swings

Depression

50% discontinue because of unpredictable or unacceptable bleeding due to:

non-adherence to therapy

Drug interactions,

For sequential regimens ◦ it is heavy or prolonged at the end of or after the

progestogen phase, or

◦ occurs at any time (breakthrough bleeding)

for continuous combined regimens ◦ if it occurs after the first six months of treatment

◦ it occurs after amenorrhoea.

altering the progestogen component of the regimen ◦ increase the duration or dosage of the progestogen

◦ change the type of progestogen

using the levonorgestrel-releasing intra-uterine system combined with an estrogen.

Recent media reports have presented conflicting stories about the safety of HRT

Varied interpretations of the different studies which have appeared in recent years.

The Society of Obstetricians and Gynaecologists of Canada has challenged

the notion that hormone therapy does more harm than good

Suggests that many women experiencing troublesome symptoms have been scared away from HRT due to misunderstandings about risks.

Beast cancer

Heart disease

Thrombosis

Endometrial cancer

The evidence suggests that combined oestrogen and progestogen preparations increase the risk of breast cancer more than oestrogen alone.

Women taking HRT should be advised to attend regularly for mammographic screening.

HRT is contraindicated in women with previous breast cancer.

The risks are statistically small and appear to be linked with the duration of therapy 5 years

Researchers also found that women can quickly reduce their risk of breast cancer by stopping HRT

The Society of Obstetricians and Gynaecologists of Canada has noted that risk factors for breast cancer, such as hormones, should be evaluated in light of equally important risk factors related to lifestyle.

Follow-up of over 1 million women currently using HRT are more likely to develop breast cancer than those who are not using HRT.

Combined HRT were at 2 fold increase

Estrogen only 1.3 fold risk.

Use of HRT by women aged 50–64 in the UK in the decade from 1993-2003 resulted in an estimated 20,000 extra breast cancers.

Mammography may not detect breast cancer. Approximately one-quarter of women taking

combined oestrogen and progestogen preparations will show a significant increase in mammographic density.

This increase in density has been shown to reduce the sensitivity of screening mammography and to increase the likelihood that women are recalled for further investigations after mammography (even if they are not found to have breast cancer).

HRT has not shown benefit in either primary or secondary prevention against ischaemic heart disease or stroke.

There is increased risk of stroke and an early excess risk of myocardial infarction in HRT users.

The absolute risk of these conditions increases with age. (WHI study)

HRT is contraindicated in women with clinical evidence of ischaemic heart disease, cerebrovascular disease or peripheral arterial disease.

WHI study linked the risk of developing heart disease to combined HRT

younger women (50 -59) taking HRT over a period of 10 years have shown no increased risk of developing heart disease (Rossouw et al, JAMA 2007; 297: 1465-77).

Combined HRT increases cardiovascular and thromboembolic risk when treatment begins many years after the menopause

Study of 5,692 women from UK, Australia and New Zealand found a significant increase in the number of "major cardiovascular events", such as angina, heart attack or sudden heart death, and potentially dangerous blood clots in the group given HRT, compared with those given placebo pills.

The study also found a decreased risk of osteoporotic fracture

No difference in the risk of stroke or cancers.

The study recommends further research to gauge the long-term risks and benefits of starting HRT near the menopause.

It must be noted that this study was stopped upon the publication of the first WHI study which revealed a link between CVD and HRT.

HRT: Counselling the risk of thrombosis (DVT clots in lung)

Prior to commencing HRT, a personal history and a family history of VTE in a first- or second-degree relative should be obtained.

HRT should be avoided in women with multiple pre-existing risk factors for VTE.

Non-oral oestrogen may be associated with lower risk of VTE, compared with oral oestrogen therapy.

Universal screening of women for thrombophilic defects prior to HRT is inappropriate.

HRT is not recommended in high-risk situations such as type 1 antithrombin deficiency or with combinations of defects

If a woman on HRT develops a VTE, HRT should be discontinued.

HRT should be considered a risk factor for VTE preoperatively. However, HRT does not require to be routinely stopped prior to surgery.

Recent randomised controlled trials in women of 65 years or older reported that HRT does not have a beneficial effect on cognitive function. Also, HRT does not appear to be an effective treatment of established Alzheimer's disease.

HRT should not be used, and is not licensed, as a primary treatment for clinically significant depression or dementia. Some, but not all, studies have shown that HRT appears to improve depressed mood in women with menopausal symptoms.

Postmenopausal women who have been taking sequential oestrogen-progestogen therapy for more than five years and wish to continue are at increased risk of endometrial carcinoma. They should consider changing to a continuous combined regimen, which appears to confer no increased risk.

Concern over the adverse effects associated with traditional HRT has led to an increase in demand for alternative treatments.

The enthusiasm directed towards alternative treatments for menopausal symptoms is understandable, but the full risks and benefits of these alternatives are still unknown.”

Over 200 preparations .

Overall symptom reduction 50-60% vs. 80-90% Traditional HRT

Soya and Red clover may have beneficial effects on the skeleton and cardiovascular system.

Long term safety and interactions with other medications??

The herb black cohosh has been linked to liver toxicity and in one instance a patient subsequently required a liver transplantation after a severe adverse reaction.

The European Union Directive has made progress in tightening safety and standards, making it mandatory for herbs to be registered, although the lack of supporting research data and evidence has so far held back licences; once granted, patients and health professionals will be able to have greater confidence in these products.

Use the lowest dose for the shortest period of time.

Risks associated with the use of HRT are low and duration of use may, if necessary, be extended

Starting HRT at the early onset of the menopause, and carrying on for a few years apparently carries little risk in healthy women.

HRT confers some benefit to bone strength and a small reduction in the risk of colonic cancer.

Tailor treatment to individual patients.

Thank you