Sheila is 35, and has been on the combined oral contraceptive pill since the age of 18. She has now stopped the pill, and when her periods did not return after 3 months, she consulted her general practitioner. A blood test has shown that she has a very high level of follicle stimulating hormone (FSH). Her physician explains that she has undergone a “premature menopause,” and will not be able to conceive. She is referred to you for an expert opinion.
“Premature menopause” or more accurately “premature ovarian insufficiency” (POI) remains poorly understood and under-researched . It describes a syndrome consisting of early cessation of menses, sex steroid deficiency and significantly elevated levels of the pituitary hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH) in women below the age of 40. Premature ovarian insufficiency can be primary (spontaneous POI) or secondary (induced by radiation, chemotherapy or surgery). Controversy persists over nomenclature with terms such “premature menopause” and “premature ovarian failure” still in usage.
Causes of spontaneous POI include idiopathic (no known cause), genetic, autoimmune and infective. The typical presentation of spontaneous POI is complete cessation of menses in a woman younger than 40 years, which may or may not necessarily be accompanied by other symptoms. These symptoms may not be typically vasomotor in nature and include mood disturbances, loss of energy and generalized aches and pains. Data indicate  that the next most disturbing aspect of POI, after the loss of fertility, is the adverse impact on sexual responsiveness and other psychological problems.
In Sheila’s case, it is possible that she had reduced ovarian reserve for a number of years, eventually leading to ovarian insufficiency. Her ovarian status and any resulting symptoms would have been masked by many years of contraceptive pill usage. There is an argument that women such as Sheila who wish to defer pregnancy until later in their reproductive years should have their ovarian reserve checked, so that they do not “miss the fertility boat” without knowing it. However, dealing with declining ovarian reserve is confusing and controversial. Sheila could have some of her oocytes collected and stored, but the whole area of “social fertility preservation” is contentious, with limited success. Furthermore, if collecting oocytes from a woman with low anti-Müllerian hormone (AMH) levels, the number suitable for freezing will be further limited.
Women also have to understand that having their ovarian reserve tested is by no means a guarantee of long-term fertility/ability to achieve pregnancy; neither is oocyte/embryo freezing.
Premature ovarian insufficiency has been estimated to affect about 1% of women younger than 40, 0.1% under the age of 30 and 0.01% of women under the age of 20. However, as cure rates for cancers in childhood and young women continue to improve it is likely that there will be more women with POI. Data from Imperial College, London suggest that the incidence of POI may be significantly higher than originally estimated. Islam and Cartwright  studied 4,968 participants from a 1958 birth cohort. They found that 370 (7.4%) had either spontaneous or medically induced POI. Smoking and low socioeconomic status were predictive of POI, and poor quality of life. The incidence of POI also appears to vary according to the population studied. It appears to be significantly higher, around 20%, in some Asian populations (personal communication from the Indian Menopause Society).
In the past, the focus of medical care has been on improving survival rates. Very little attention has been given to the maintenance of quality of life in the short term and to the avoidance of the long-term sequelae of POI. One of the main reasons for this has been the bias of economic expenditure and medical endeavor to the prolongation of life (e.g. cancer treatments) rather than towards optimizing quality of life in cancer survivors. Should this trend continue, we are in danger of creating a population of young women who have been given back the gift of life, but left without the zest to live it to its full potential. Maintenance of postmenopausal health is also of paramount importance if we are to minimize the economic impact on society in this and future generations.
Premature ovarian insufficiency has been associated with 50% higher mortality compared with menopause at age 52–55. A large prospective cohort study demonstrated significantly increased all-cause mortality in those with menopause before 40 years after adjustment for confounding factors (hazard ratio [HR] 1.4), and life expectancy was reduced by 2 years compared with women with menopause between 50 and 54 years. The Mayo Clinic Cohort Study of Oophorectomy and Aging demonstrated that mortality was significantly higher in women who had prophylactic bilateral oophorectomy before the age of 45 years (HR 1.67). This increased mortality was however limited to those who did not receive HRT up to the age of 45 years, therefore suggesting that estrogen may have a protective role.
An association between early menopause and increased mortality from cardiovascular disease has been established for many years. There is an estimated 80% increase in risk of mortality from ischemic heart disease in those with menopause before 40 years compared with those with menopause at 49–55. The risk of ischemic heart disease is more pronounced in never-users of HRT. The Danish Nurses Cohort Study showed that the risk of ischemic heart disease was greater after a surgical menopause rather than spontaneous POI. This mechanism is probably due to the profound loss of ovarian hormones resulting in insulin resistance, reduced arterial compliance and atherosclerosis.
The detrimental effects of declining estrogen levels on bone density in menopausal women have long been recognized. Women with POI have significantly lower bone density compared with controls. Both spontaneous and iatrogenic early menopause result in lower bone mineral density compared with controls and this is associated with a significantly higher fracture risk.
The Mayo Clinic Cohort Study of Oophorectomy and Aging has shown an increased risk of cognitive impairment in women having premenopausal oophorectomies and that this risk increases the younger it is performed. There is some evidence from the same study that HRT may reduce this risk. Definitive conclusions regarding the risk of cognitive impairment in POI cannot yet be drawn due to a lack of data in women under the age of 40 and in those with non-surgical etiologies.
Women such as Sheila with POI require integrated care to address physical, psychosocial and reproductive health, as well as preventative strategies to maintain long-term health. However, there is an absence of evidence-based guidelines for diagnosis and management. Premature ovarian insufficiency is a difficult diagnosis for women to accept, especially when it occurs before child-bearing has been completed and a carefully planned, sensitive approach is required when informing the patient of the diagnosis. A dedicated multidisciplinary clinic separate from the routine menopause clinic will provide Sheila with ample time and the appropriate professionals to meet her emotional needs at such a traumatic time. At the West London Menopause Centres we have restructured our services to create dedicated clinics for POI patients.
Counseling should include explanation that remission and pregnancy can still occur in women with spontaneous or medical POI. Specific areas of management include the provision of counseling and emotional support, diet and nutrition supplement advice, hormone replacement therapy and reproductive health care, including contraception and fertility issues. There is an urgent need for large-scale, long-term randomized prospective studies to determine the optimum routes and regimens of hormone replacement therapy. Outcome measures should include relief of short-term symptoms such as vasomotor, urogenital and psychosexual issues, and the long-term effect on cardiovascular, cognitive and skeletal health.
As a minimum, the initial investigation of patients presenting with absent or infrequent menses include exclusion of pregnancy, measurement of serum FSH, estradiol, prolactin, androgens and thyroid hormones. If FSH is in the menopausal range (> 40 IU/mL) in a woman younger than 40, the test should be repeated a minimum of 4 weeks later for confirmation, as levels can fluctuate. Estradiol levels also fluctuate and results should be interpreted in conjunction with FSH. Sheila should not be definitively informed that she has had a premature menopause before a repeat test has been performed to confirm the diagnosis.
Evaluation of other hormones of ovarian origin, such as inhibin B and AMH, and the ultrasonographic estimation of the antral follicle count can also be used to assess ovarian reserve, but these are not essential in making the diagnosis. Some studies suggest that the precise age of menopause transition can be predicted through the use of these biomarkers; this requires confirmation, especially in POI, and is discussed in greater detail in Chapter 2.
It is essential that a detailed personal and family history is taken from patients such as Sheila. There is often a family history of spontaneous POI in first-degree relatives (around 30–40% of cases). Karyotyping and fragile X testing for the FMR-1 gene mutation will detect the most common genetic causes of spontaneous POI (Turner’s syndrome and fragile X syndrome), but these constitute the minority of causes of spontaneous POI. In the long term, the polygenic inheritance of risk for spontaneous POI is likely to be unraveled and banks of genes will be tested to give an individual the precise risk of POI.
It has been estimated that 20% of women with POI have associated autoimmune thyroid disease and 3% have autoimmune adrenal disease; it is therefore important that thyroid and adrenal antibodies are checked and if present, further tests of thyroid and/or adrenal function should be carried out. In view of the increased long-term risk of osteoporosis, a baseline dual energy X-ray absorptiometry (DXA) bone density scan should be carried out and repeated every 2–5 years depending on the results. Table 25.1 summarizes the key investigations in POI.