Premature Menopause

Premature menopause occurs when ovaries stop working at a young age, less than 40. This is at least 10 years earlier than the average age of the menopause. Because of the loss of ovarian follicular activity, levels of the female hormone, oestrogen, drop to very low levels.

Ovarian activity reflects the activity of the follicles that make up the ovaries. Each follicle consists of an egg surrounded by an outer covering of cells known as follicular cells. The egg is important for fertility whereas follicular cells produce hormones. Monthly development of ovarian follicles leads to the release of an egg (ovulation) and to the production of the two female hormones, oestrogen and progesterone. These hormones act on the womb lining causing it to thicken and then to break down, and are therefore responsible for bringing about menstrual bleeding. Females are born with a fixed quota of ovarian follicles (~1-2 million), the numbers of which become less and less throughout life. Eventually, follicle numbers drop to very low levels (less than 1000) leading to a fall in circulating hormone levels, the stoppage of periods, and consequently, the menopause.

Premature menopause therefore represents the transition into an oestrogen-deficient and infertile state at an early age.
For more information on follicles, hormones and ovulation see my sections on The Menstrual Cycle and Ovulation Cycle Tracking and Anovulation and Ovulation Induction.

The European Society for Human Reproduction and Embryology (ESHRE) developed guidelines for diagnosing and managing premature menopause in 2016.

For diagnosing premature menopause, the following are required:

1. Stoppage of periods for at least 4 months in women under 40
2. Two blood tests at least 4 weeks apart showing increased levels (above 25 IU/L) of the hormone FSH

In patients with premature menopause, there is a higher chance of having problems with the adrenal and the thyroid glands. It is recommended to test for auto-antibodies against the thyroid and adrenal glands.

Because of the effects of oestrogen deficiency on bones, a specialised X-Ray to assess bone mass (DEXA) should be performed.

The symptoms of premature menopause are similar to those of a natural menopause at 50. In women with premature menopause, the symptoms may be more severe. They include vasomotor symptoms (hot flushes and night sweats), mood changes, sexual dysfunction, vaginal dryness and urinary problems. For more details, see my section on Menopause.

Premature menopause often happens unexpectedly and remains a very mysterious condition. It may sometimes be caused by certain medical treatments. Smoking has been associated with an earlier menopause but does not typically cause premature menopause. A number of different genetic mutations have been associated with POI but in most cases, the underlying cause is unknown.

Surgery on the ovaries:
Ovaries may be intentionally removed, for instance, to reduce the risk of cancer related to an inborn genetic risk (e.g. BRCA1/2 gene mutation). In some cases, ovaries may become severely damaged due to surgery on the ovaries (e.g. for treating ovarian cysts or extensive endometriosis).

Cancer treatment:
Another very important cause of damage to ovaries is treatment for cancer such as chemotherapy. Chemotherapy blocks the survival of cancer cells by causing damage to their genetic material (or DNA). Unfortunately, eggs in the ovary are also very sensitive to the damaging effects of chemotherapy. Some chemotherapy drugs (e.g. the alkylating agents) are especially dangerous to the ovaries. For these reasons, prior to undergoing cancer treatment, reproductive-aged women should be referred to a fertility specialist to discuss options for fertility preservation.

Genetic and unknown causes:
In most cases, the underlying cause for premature menopause is unknown.
In rare instances, females may be born with genetic changes that predispose to the early loss of eggs. In extreme cases, like most instances of Turner syndrome (these girls are born with only one X chromosome instead of two), the ovaries may not have any eggs from birth. In other instances, there may be eggs at birth, but they then undergo an early decline leading to premature menopause.
Some medical conditions and a number of genetic mutations have been found to be associated with an early decline in egg numbers. Some examples are Galactosemia, the Fragile X premutation and BPES (Blepharophimosis-Ptosis-Epicanthus inversus Syndrome).

Very early loss of ovarian function is very distressing and has significant psychological effects.
It signals the loss of fertility and loss of circulating oestrogen. If not recognised early, lack of oestrogen has major consequences for physical and mental wellbeing.
Without oestrogen replacement, women with premature menopause have higher rates of heart disease, severe thinning of the bones and problems with brain function (e.g. memory). Premature menopause also reduces life expectancy, mostly because of increased heart disease.

Treatment is required for the two major consequences of premature ovarian failure – the lack of oestrogen and infertility.

Treatment for oestrogen lack:
Lifestyle changes are important to minimise the risks for heart and bone problems. This includes stopping smoking, undertaking regular exercise and maintaining a healthy diet and weight. It is important to ensure adequate calcium and vitamin D intake, and if dietary intake is inadequate, supplements should be used.

Drug treatment involves hormonal therapy with oestrogen. Systemic oestrogen treatment (e.g. tablets and patches) is essential to prevent the problems outlined in prior sections such as heart disease and bone thinning. Treatment should be continued at least until the age that natural menopause would occur, that is, 50.
Hormone treatment follows similar principles as for hormonal treatment after a natural menopause. For more details, see my section on Menopause.
Progesterone is only required for women who have a womb in order to protect the womb lining from the effects of oestrogen. Progesterone is not needed if the womb has been removed by hysterectomy.
The combined oral contraceptive pill is an option for replacing oestrogen in young women with premature menopause provided there are none of the usual risk factors (e.g. smoking). However, the pill contains so-called “synthetic” oestrogen formulations (ethinyl oestradiol) and preparations containing oestrogens that are more like those found in the body (17β oestradiol) are preferred.
Vaginal oestrogen and/or vaginal lubricants may also be required if vaginal symptoms (e.g. dryness and painful sexual intercourse) persist with systemic oestrogen treatments.
For a full discussion surrounding the range of treatments, including the various oestrogen preparations and treatments for thin bones, see my section on Menopause.

Treatment for infertility:
Premature menopause occurs because the ovaries have become depleted of follicles, and hence no longer contain eggs. Very occasionally, there may be very transient episodes of ovarian activity and follicular development that lead to the release of an egg. Because of this, pregnancy may occur in 1-5% of cases of premature menopause.
For more information on follicles, hormones and ovulation see my sections on The Menstrual Cycle and Ovulation Cycle Tracking and Anovulation and Ovulation Induction.
In most cases, however, premature menopause reflects an absence of eggs. Because there are no more eggs in the ovary, no treatment, including IVF, will be successful. Treatment to achieve a pregnancy will require the use of eggs donated from another woman. For more information on donor egg treatment see my section on Donor Treatment.

No, the risks are less for women who have had a premature menopause and are using oestrogen before age 50. This is because oestrogen would normally be present until age 50 so oestrogen in cases of premature menopause is simply being used as a replacement strategy. This is true “hormone replacement” (or HRT) whereas hormone treatment after the natural menopause (age 50) involves using hormones when they are not normally present and is therefore now called Menopausal Hormone Therapy (MHT).
Hormone therapy for premature menopause does NOT increase the risk of breast cancer before the age of the natural menopause.

No, there aren’t any reliable tests for predicting the age that menopause will occur.
Female relatives of women who have undergone premature menopause are on average more likely to have an earlier menopause. In the very few instances in which a genetic mutation has been identified as the cause of premature ovarian insufficiency, female relatives can seek genetic counselling and be tested for the specific genetic mutation.
A blood test for AMH (or Anti-Müllerian Hormone) has been suggested to be able to predict when someone might enter the menopause. However, studies have produced very contradictory results regarding the usefulness of AMH for this purpose. At present, AMH is not recommended for predicting menopause onset. This year, the American College of Obstetricians & Gynaecologists (ACOG) concluded that “the use of antimüllerian hormone as a predictor of the onset of the menopause is unsuitable for clinical practice at this time”.
For more information on AMH, see my section on AMH, Ovarian Reserve and the Egg Timer Test.

It is first important to make the correct diagnosis since many cases in which menstrual periods stop prematurely are not because of failure of ovarian activity. Premature menopause has many causes and different treatment needs. In all cases, oestrogen replacement and close monitoring for development of problems such as thin bones are required. In some cases of premature menopause (e.g. Turner syndrome), more than one type of specialist input is required for managing the associated medical conditions. Managing the fertility component of premature menopause requires extensive expertise in infertility treatments, including the use of donor eggs.

If you have concerns about premature menopause, it is very important to see a specialist who is fully up-to-date with the latest information, and who can evaluate your individual circumstances in order to devise the safest and most effective plan suited to you. Prof Homer is a Sub-specialist in Reproductive Endocrinology and has extensive expertise in hormonal treatment and conducting fertility treatments (including Donor Treatment). He worked and trained in one of the UK’s largest clinics at University College London Hospitals dedicated to treating patients with premature menopause due to Turner syndrome, cancer treatments and unknown causes.