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Fact Sheets: Article

Title: Premature Menopause

Women with a premature menopause are usually advised to have hormone replacement therapy until the average age of the natural menopause (52). This advice is unchanged by the Women's Health Initiative and Million Women studies which were both undertaken in women aged 50 and over. There is no evidence that hormone replacement therapy (HRT) increases risk of breast cancer, cardiovascular disease or dementia over and above that found in menstruating women with a normally timed menopause.

Background

Premature menopause should be defined ideally as menopause that occurs at an age less than two standard deviations below the mean estimated for the reference population. The age of 40 years is frequently used as an arbitrary limit, but many gynaecologists take <45 yrs.

Primary premature ovarian failure

Primary premature ovarian failure can occur at any age, even in children. It can present as either primary or secondary absence of periods (amenorrhoea). In the great majority of cases no cause can be found.

Causes of premature menopause

*Chromosome abnormalities: particularly of the X chromosome have been implicated

* Autoimmune disease: autoimmune endocrine disease such as hypothyroidism, Addison's disease and diabetes may be associated with premature ovarian failure.

* FSH receptor abnormalities: mutations of gonadotrophin receptors have been reported.

* Disruption of estrogen synthesis: specific deficiencies of enzymes such as 17 alpha hydroxylase, can prevent estradiol synthesis leading to primary amenorrhoea and elevated gonadotrophin levels even though developing follicles are present.

* Metabolic galactosemia is associated with premature ovarian failure. It is thought that galactose and its metabolites may be toxic to the ovarian parenchyma.

Secondary premature ovarian failure

* Radiotherapy and chemotherapy. Chemotherapy can cause either temporary or permanent ovarian damage, depending on the cumulative dose received and duration of treatment; long term treatment with small doses being more toxic than short term acute therapy. These effects occur at all ages, but especially so in women aged more than 30 years. With regard to radiotherapy, ovarian damage is dose and age dependent.

* Bilateral oophorectomy or surgical menopause results in an immediate menopause which may be intensely symptomatic.

* Hysterectomy without oophorectomy can induce ovarian failure either in the immediate postoperative period, where in some cases it may be temporary, or at a later stage where it may occur sooner than the time of natural menopause. This is an area of controversy and may depend on ovarian function preceding hysterectomy. The diagnosis may be difficult since not all women suffer acute symptoms, and in the absence of a uterus the pointer of amenorrhoea is absent. A case could be made for annual FSH estimation in women who have had a hysterectomy before the age of 40.

* Infection may rarely affect the ovaries. Tuberculosis and mumps are infections which have been implicated. In most cases normal ovarian function occurs after mumps infection.

Consequences of premature menopause

Women with untreated premature menopause are at increased risk of developing osteoporosis, cardiovascular disease, dementia, cognitive decline and Parkinsonism and all cause mortality.

Treatment

HRT is normally recommended until the average age of the natural menopause (52) The regimens used will depend on whether the woman has undergone hysterectomy or not, or whether she still has some ovarian activity and still has periods. Women with an early menopause, especially if surgically induced, may need to have a higher dose of estrogen to control their vasomotor symptoms.

Spontaneous ovarian activity may recur with the resulting fertility implications. Thus it can be very difficult to be able to advise women as to when they do not need contraception.

There is no evidence that HRT increases risk of breast cancer and cardiovascular disease over and above that found in menstruating women with a normally timed menopause for this age group [ <52 yrs].

Further reading

Committee on Safety of Medicines ( CSM) December 2003. Further advice on safety of HRT: risk benefit unfavourable for first-line use for prevention of osteoporosis.
Jacobsen BK, Heuch I, Kvale G. Age at natural menopause and all-cause mortality: a 37-year follow-up of 19,731 Norwegian women. Am J Epidemiol 2003;157:923-9

Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362: 419-427.

Pitkin J, Rees MC, Gray S, Lumsden MA, Marsden J, Stevenson JC, Williamson J.Management of premature menopause. Menopause Int 2007;13:44-5.

Rocca WA, Grossardt BR, de Andrade M, Malkasian GD, Melton LJ 3rd. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol 2006;7:821–8.

Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grossardt BR, de Andrade M, Melton LJ 3rd. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology 2007;691074-83.

Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grossardt BR, de Andrade M, Melton Iii LJ. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2007 Aug 29; [Epub ahead of print]

Tucker D. Premature ovarian failure. In: Rees M, Hope S, Ravnikar V. The Abnormal Menstrual Cycle. Abingdon: Taylor and Francis; 2005. p. 111–22.

van Der Voort DJ, van Der Weijer PH, Barentsen R. Early menopause: increased fracture risk at older age. Osteoporos Int 2003;14:525-30.

van der Schouw YT, van der Graaf Y, et al. Age at menopause as a risk factor for cardiovascular mortality. Lancet 1996;347:714-8.

Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288: 321-33.

Margaret Rees

Sally Hope

John Stevenson

March 2005 reviewed January 2008.

Whilst great care has been taken to ensure the accuracy of information contained in the fact sheets, the authors and the BMS cannot accept any responsibility for any errors omissions, mis-statements or mistakes or for any loss or damage arising from actions or decisions based on information contained in this publication. Ultimate responsibility for the treatment of patients and interpretation of published material lies with the medical practitioner. The opinions expressed are those of the authors, not necessarily those of the BMS. The inclusion in the publication of material relating to a particular product, method or technique does not amount to an endorsement of its value or quality, or of claims made by its manufacturer.
Margaret Rees and Sally Hope January 2008

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