Introduction

Delayed diagnosis, menopausal symptoms, infertility, increased risk of cardiovascular disease (CVD) and osteoporosis are just some of the issues confronting young women with premature menopause (PM). Psychological distress including depression, altered body image and ‘feeling old before my time’ is also commonly experienced.

Menopause occurring before the age of 40 years is defined as premature and includes spontaneous and medically/surgically induced menopause. The terms premature menopause (PM) and premature ovarian failure (POF) are often used interchangeably.

Author   Dr. Amanda Vincent MBBS, B.Med. Sci., PhD, FRACP Endocrinologist, Southern Health Menopause Unit, Melbourne; Research Fellow, Jean Hailes Research Unit, Monash University

Approximately 1 per cent of women under 40 years experience spontaneous PM, rising to 8-10 per cent where PM results from surgery or chemo/ radiotherapy. Early menopause (EM) occurs between 40-45 years and affects 5 -10 per cent of women. Observational studies have identified family history, smoking, poor response to ovarian stimulation and epilepsy as risk factors for spontaneous PM.

The cause of spontaneous PM is unknown in the majority of women (60 per cent of cases in one series) and is classified as karyotypically normal spontaneous POF. Known causes of PM are listed (table 1) and include potentially any pelvic surgery via disruption of ovarian blood supply or inflammation. Clinical or sub-clinical (detection of auto-antibodies only) manifestations of autoimmune disease may be present, with thyroid disease the most common association (reported in 27 per cent of women in one study). The rate of chemotherapy-induced PM depends on age, cumulative dose, duration and agent involved.

Clinical Presentation

PM may develop acutely or gradually and each woman may present different. Vasomotor symptoms are present in 50 per cent of women. Following oophorectomy onset of severe vasomotor symptoms often occurs. A common scenario is the onset of amenorrhoea and/or vasomotor symptoms after cessation of the oral contraceptive pill (OCP). Other symptoms can be experienced and may be more severe than in the typical menopausal women (table 2).

Diagnosis

PM should be considered with secondary amenorrhoea or menstrual disturbance regardless of menopausal symptoms. While the clinical presentation of PM may be similar to perimenopause, the diagnosis is often delayed because the woman is considered too young. The median time to diagnosis has been reported as two years and 61 per cent of women consulted three or more clinicians prior to diagnosis. A high index of suspicion should be maintained in women with risk factors.

Clinical assessment including history (table 2) and examination provides information regarding aetiology, assessment of hormone deficiency and related complications.  

Table 2 : History

Presenting symptoms menstrual disturbance menopausal pregnancy/infertility galactorrhoea

Gynaecolgical history pubertal development menarche menstrual history parity previous gynaecological surgery including surgery for endometriosis, hysterectomy and oophorectomy

History or symptomatology of autoimmune disorders especially adrenal or thyroid dysfunction

Past history history of inherited conditions such as Turner's syndrome previous cancer and treatment including radiotherapy or chemotherapy history of viral infections including mumps and cytomegalovirus eating disorder cardiovascular disease risk factors osteoporosis

Exclude causes of secondary amenorrhoea

Medication for example OCP, chemotherapy, antipsychotics

Family history of PM, autoimmune disorders, cardiovascular disease, osteoporosis

Lifestyle assessment smoking alcohol intake diet exercise pattern

Laboratory investigations: The diagnostic criteria for POF include greater than four months of amenorrhoea and FSH levels >40IU/L on two separate occasions at least one month apart with exclusion of secondary causes of amenorrhoea. Gonadotrophins should be measured (in the absence of exogenous hormones e.g. OCP). There is no test to predict PM. Pelvic ultrasound may be useful.

Management

1. Psychological issues

Women with PM appear to have greater depression and anxiety, low self esteem and impaired sexual function. Experiencing menopause outside normal life stage is likely to be distressing. The individual social situation will impact on experiences. Counselling and listening are beneficial and referral to a psychologist/psychiatrist may be necessary.

2. Education and Information

Patient satisfaction is related to time and empathy in consultation. Compliance with hormone replacement therapy (HRT) is dependent upon understanding the consequences of oestrogen deficiency. Resources are available to assist with education (see Useful Websites).

3. Diet and Lifestyle

Modification of dietary and lifestyle factors assist both psychological and physical symptoms and reduces cardiovascular disease and osteoporosis risk.

4. Hormone Replacement Therapy (HRT)

HRT for oestrogen deficiency symptoms in the absence of contraindications, is generally accepted. Early initiation and continuation until approximately 50 years of age is appropriate. However, there is no specific data in PM. The Women's Health Initiative (average age 63 years) led to reluctance to use HRT, even in young women. However, key professional societies recommend this data should not be extrapolated to young women.

There is no consensusregarding optimal HRT in PM, although higher doses of oestrogen (equivalent to 1.25mg conjugated equine oestrogen) may be needed. Monthly withdrawal bleeding can be psychologically important. Where a woman with POF desires contraception, the low dose oral contraceptive pill may be considered.

5. Androgen Therapy

Female androgen insufficiency syndrome (FAIS) is described with clinical and biochemical features (low testosterone levels). Positive effects of testosterone therapy have been demonstrated short term. However, androgen replacement remains controversial and there are currently no TGA approved testosterone preparations specifically for women available in Australia.

6. Non-hormonal therapies

Non-hormonal therapies for the treatment of vasomotor symptoms can be considered in PM. A recent meta- analysis of non-hormonal therapies including antidepressants, antihypertensives, gabapentin, red clover and soy isoflavone extracts provided supportive evidence for efficacy of paroxetine, venlafaxine, gabapentin and clonidine (and mixed results for soy isoflavones) in reducing hot flushes. However, benefits were small and long term efficacy and safety is unknown. Women with breast cancer may experience hot flushes due to chemotherapy induced EM/PM, oophorectomy  and/ or secondary treatment with tamoxifen/ aromatase inhibitors. Non-hormonal therapies may be useful in this setting; however paroxetine may interfere with tamoxifen. The efficacy and safety of herbal/ complementary preparations is not established.

7. Fertility

Spontaneous remission is observed in POF with a lifetime chance of conception of 5-10 per cent. Currently the only proven therapy for obtaining a pregnancy is via use of donor oocyte. The option of freezing embryos/eggs or ovarian tissue should be considered prior to chemo/ radiotherapy.

8. Long Term Sequelae

Women with PM are at risk of long term complications and monitoring is needed.

(i) Monitoring of the long term complications associated with specific causes of PM (eg. Turner's syndrome) is necessary. Although the natural history of associated autoimmune dysfunction is unclear, yearly TFTs and fasting glucose is recommended.

(ii) CVD risk is increased and monitoring and treatment of risk factors is recommended.

(iii) Osteopaenia is common and risk factors need to be considered. Therapy follows conventional measures. HRT is indicated but the role of other agents including bisphosphonates is less clear.

(iv) Recurrent malignancy is a concern where PM is secondary to cancer therapy.

Management summary

• Prompt and accurate diagnosis
• Inform in a sensitive and supportive manner
• Counseling especially in relation to fertility
• Identify and address psychological issues
• Institute HRT or appropriate alternative
• Assess and monitor for the presence of long term sequelae and institute appropriate treatment
• Referral to a support group and/or provide educational material

Useful websites:

www.jeanhailes.org.au

www.menopause.org.au

www.endocrineonline.org.uk

www.menopause.org

www.pofsupport.org

ACCESS: Australia's National Infertility Network www.access.org.au

www.daisynetwork.org.uk

Suggested reading

1. Alzubaidi N,Chapin H, Vanderhoof V et al., Meeting the needs of young women with secondary amenorrhea and spontaneous ovarian failure. Obstet Gynecol 2002; 99:720-725.

2. Anasti J, Kalantaridou S, Kimzey et al., Bone loss in women with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol 1998; 91: 12-15.

3. Goswami D and Conway GS, Premature ovarian failure. Hum Reprod Update 2005;11: 391-410

4. Kalantaridou SN, Naka KK, Bechlioulis A et al., Premature ovarian failure, endothelial dysfunction and oestrogen-progestogen replacement.. Trends In Endocrinol Metab 2006; 17: 101-109.

5. Liao K, Wood N, Conway G. Premature menopause and psychological well-being. J Psychosom Obstet Gynaecol. 2000; 21:167-74.

6. Nelson HD et al., Non-hormonal therapies for menopausal hot flashes. JAMA 2006 295:2057-207. (www.jama.com))

7. North American Menopause Society. Estrogen and progestogen use in the peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause. 2007; 14:1-17.

8. North American Menopause Society. Testosterone therapy in postmenopausal women: position statement of The North American Menopause Society. Menopause. 2005; 12:497-511.

9. Schouver L. Premature ovarian failure and its consequences: vasomotor symptoms, sexuality and fertility. J Clin Oncol 2008; 26:753-758.

10. Sherwin B. Estrogen and cognitive functioning in women. Endocrine Reviews 2003;24:133-151

Content Updated May 9, 2008