What are the blood tests for menopause?

There are many new tests for menopause and for assessing hormone replacement therapy (HRT) requirements. What are the best tests, what do the results actually mean and why is it best to get expert help?

A common menopause blood testing profile will often include the following test requests:

• Oestrogen or E2
• FSH
• LH
• Progesterone
• FTEST (Free testosterone)
• DHEA-S
• Anti-Müllerian hormone (AMH) and the countdown

Why are these tests requested and what do the results actually tell you?

The hormones, oestradiol and progesterone, are made by the ovaries in a cyclical fashion that help to maintain a normal menstrual cycle. When a woman reaches menopause, cyclical hormone production from the ovaries stops, leading to a cessation in monthly menstrual periods and of egg production.

The menopausal change is slow and usually takes two to five years to complete. During this so-called peri-menopausal phase (also sometimes referred to as ‘the climacteric’ or ‘the change’), hormone levels can fluctuate from high to low and from one month to the next.

Some months a woman may have a period but then go for several months without a period. It is important to note that during this time, a woman may still be able to get pregnant. Menopause is said to have taken place when a woman has not had a period for 12 months.

Menopause happens naturally as a woman ages. However, menopause can also occur for other reasons, including the removal of the ovaries for cancer or other medical reasons like endometriosis.

The diagnosis of menopause is usually made on clinical grounds, i.e. symptoms and history. The following biochemical investigations may be performed on blood when menopause is suspected but the diagnosis is not clear:

• Follicle-stimulating hormone (FSH), to learn whether she is approaching or has gone through menopause
• Oestradiol, to measure ovarian production of oestrogen and to further assist in determining menopausal state
• Thyroid function testing (T4 and TSH tests) to assess the function of the thyroid gland
• Assessment of liver and kidney function

Oestrogen (US - Estrogen) and oestradiol (E2)

Oestrogen consists of three hormones (E1, E2 and E3), that fundamentally regulate the development of the female sex organs (and secondary sex characteristics). Oestradiol (E2) is mainly produced in the ovary in women and therefore levels of E2 start to fall at the menopause. Normal levels of oestradiol are important for ovulation.

E2 production is stimulated by Follicular Stimulating Hormone (FSH), which is produced by the pituitary gland. FSH stimulates the follicles surrounding the eggs in the ovaries, causing them to produce E2. When the oestrogen concentrations reach a certain level, the hypothalamus part of the brain produces Luteinising Hormone (LH).

The role of LH is to cause the release of the egg into the womb ready for fertilisation. Oestrogens are utterly fundamental especially as they can also have effects on blood coagulation, lipid metabolism and as explained by the UK's pioneer into HRT, Professor John Studd - for maintaining collagen and bone density.

In summary then; FSH stimulates the follicles in the ovaries to produce E2. On reaching a certain level, E2 will stimulate the production of LH, which causes the egg to be released.

A blood sample is required to measure oestrogen. No test preparation is needed, but the timing of the sample will be checked by your doctor in order to correlate with your menstrual cycle.

Levels of oestrogen can fluctuate as a result of many metabolic conditions, hypertension and anaemia. It is therefore absolutely essential that care must be used in the interpretation of oestrone (E1), oestradiol (E2), and oestriol (E3) levels because their levels will vary widely on both a daily basis - and throughout the menstrual cycle.

Single results on their own may be relatively meaningless. Your doctor will be interested in trends with rising or falling results over time. A diagnosis cannot be made solely based on one test result.

Follicle Stimulating Hormone (FSH) - follicular and luteal phases

Control of FSH (and LH) production is regulated by oestradiol from the ovaries. As mentioned (above), FSH stimulates the growth and the development of unfertilised eggs during the 'follicular phase' of the menstrual cycle.

This cycle is divided into two phases, the follicular and the luteal, by a mid-cycle surge of FSH and LH. Ovulation - when the egg is released from the ovary occurs shortly after this mid-cycle surge of hormones.

FSH initiates the production of E2 by the follicle, and both hormones help to develop the egg follicle. During the luteal phase, FSH then stimulates the production of progesterone.

Rising FSH?

Both E2 and progesterone help the pituitary control the amount of FSH produced. At the time of the menopause, the ovaries stop functioning and FSH levels rise. During pregnancy, oestrogen levels are high and this makes FSH undetectable.

A blood sample is needed to test the FSH level. The sample should be taken in the first 4 days of the cycle if the periods are regular (day 1 is the first day of full bleeding). If the test is for the menopause, for example, and periods are stopping then the FSH can be taken at any time but occasionally repeat samples may be needed.

It can take a couple of years for the ovaries to stop working completely and results may be contradictory when the menopause first starts to occur. It is therefore important to note that the FSH test should not be performed if taking female hormones (for example contraceptives such as the combined oestrogen and progestogen or high-dose progestogen pill) as the presence of these hormones will also affect the interpretation of results.

When a woman enters the menopause and her ovaries stop working, FSH levels will rise. This is a normal process with the average age in the UK of onset estimated at 51 years old.

The normal age range is very wide and some women are affected by Premature Ovarian Insufficiency (POI) or Premature Menopause. Senior gynaecologist specialising in menopause, Mike Savvas explains, "Menopause usually occurs around the age of fifty but it can occur much earlier. In 1% of women it occurs before the age of forty and this is termed Premature Ovarian Insufficiency (POI) or Premature Menopause. In 0.1% of women it occurs before the age of thirty".

Low levels of FSH and LH with low levels of oestrogen are consistent with secondary ovarian failure due to a pituitary or hypothalamic problem, which is why other hormones such as TSH and FT4 are often included in menopause blood testing profiles.

Dr Caje Moniz, Consultant Clinical Biochemist and Head of Biochemistry at King’s College Hospital commented: “The menopause is a result of a loss of ovarian function. When approaching the menopause, periods become irregular, FSH levels increase in an attempt to stimulate the ovaries and overcome the negative inhibition that they normally exert.”

He added: “Measuring FSH in the blood can give an indication of ovarian status and whereas levels fluctuate during normal periods , this fluctuation increases 4-5 fold at the climecteric".

Luteinising hormone (LH)

There is a mid-cycle surge of FSH and LH. The high level of LH at mid-cycle triggers ovulation. LH also stimulates the ovaries to produce other hormones, mainly E2 and progesterone. E2 helps the pituitary gland to control the production of LH. At the time of the menopause, the ovaries stop functioning and LH concentrations rise.

A blood sample is required and should be collected at specific times during the menstrual cycle - usually the first phase.

Progesterone, period or pregnancy

Increasing oestrogen levels cause a surge in LH mid-cycle leading to the release of an egg from the ovaries. In the second half of the cycle the corpus luteum (a small yellow mass of cells) forms in the ovary at the site where the egg was released and begins to produce progesterone. This progesterone stops endometrial growth and prepares the uterus for the possible implantation of a fertilised egg. If fertilisation does not occur, the corpus luteum degenerates, progesterone concentrations fall, and the endometrial lining is shed (menstruation).

Progesterone levels peak 7 days prior to the onset of menses. If a menstrual cycles is regular and conforms to a standard 28 day length, progesterone concentrations will normally peak on approximately day 21 of the cycle (with day 1 being the first day of menstruation).

When assessing for ovulation, progesterone should be measured at day 21 of the cycle or 7 days prior to the expected onset of menses. If a woman has an irregular or prolonged cycle then progesterone can be measured on a weekly basis until the onset of menses.

If an egg is fertilised following ovulation, and becomes implanted in the uterus, the corpus luteum continues to produce progesterone. After several weeks, the placenta replaces the corpus luteum as the main source of progesterone, producing relatively large amounts of the hormone throughout the rest of a normal pregnancy.

Interpretation of progesterone test results requires accurate knowledge of where a woman is in her menstrual cycle. Progesterone concentrations in the blood usually start to rise when an egg is released from the ovary, continue to rise for several days, and then either continue to rise with early pregnancy or fall to start menstruation.

If progesterone concentrations do not rise and fall on a monthly basis, a woman may not be ovulating or having menstrual periods. 

Free or 'unattached' testosterone

Women's ovaries also make small amounts of testosterone. The hormone is involved with many organs and body processes in women. Consultant Gynaecologist, Mr Mike Savvas explains that testosterone is often thought of as a male hormone, however, it is an important protective hormone in women too.

Unlike oestrogen which declines very sharply with the menopause, testosterone, which is produced by the ovaries and the adrenal glands, starts to decline very slowly from the 20s or 30s. The level of testosterone in women in their 60s is around half that seen in women around 30 years of age. While the value of oestrogen replacement is well established the value of testosterone is often unrecognised.

Bioavailable testosterone with oestrogen

Most of the testosterone attaches to two proteins: albumin and sex hormone binding globulin (SHBG). Some testosterone is free, which means it is not attached to proteins. Free testosterone and albumin-bound testosterone are also referred to as bioavailable testosterone. This is the testosterone that is actually available for use. 

The free testosterone can help give more information when total testosterone is low. Increased levels of testosterone can indicate polycystic ovary syndrome (PCOS). This condition can cause: 

• Infertility
• Lack of menstruation
• Acne
• Obesity
• Blood sugar problems
• Extra hair growth, especially on the face

Testosterone levels are usually measured prior to commencing HRT treatment and the levels are checked during treatment to ensure that each woman receives the correct dose.

Oestrogen replacement is safe and effective in the treatment of menopausal symptoms and preventing osteoporosis but the combination of oestrogen and testosterone is better, particularly in those women who have had a premature menopause or have had their ovaries removed. It should also be considered in women who continue to experience symptoms of loss libido, depression, mood swings headaches and tiredness despite taking oestrogen.

Prior to any blood test request, your doctor will need to know about any medicines, herbs, vitamins, and supplements you are taking.

DHEA-S (dehydroepiandrosterone sulphate) and hormone deprivation

DHEA is known as a pro-hormone that I can be converted to testosterone and oestrogen. The sulphated from of DHEA, DHEAS lasts longer in the blood and its levels remain stable throughout the day. Levels are not altered significantly by the menstrual cycle. When getting a blood test for DHEAS, the fraction that is routinely measured is therefore DHEA-S. DHEA-S is rapidly converted back to DHEA when needed by the body.

DHEA levels decrease approximately 80% between ages 25 and 75 year. The most dramatic fall in blood levels of DHEA-S is between the ages of 20-30 and 40 -50 years, when levels drop by 60-70%.

Since DHEA is transformed to both androgens (sex hormones) and oestrogens, such a fall in blood levels of DHEA-S explains why there is not only a lack of oestrogens but also a likely deprivation of testosterone.

Due to the pro-hormone nature of DHEA, it can be used as an alternative form of HRT for women who have contra-indications for traditional oestrogen/progesterone HRT.

Anti-Müllerian hormone (AMH) and the countdown

AMH is considered to be the best test for measuring ovarian reserve (the number of eggs still left in the ovaries). Although the AMH test is normally used to check fertility, levels can also be used to predict the start of menopause.

Predicting time to menopause

AMH levels become low approximately 5 years before the final menstrual period, until they become undetectable when postmenopausal. AMH is therefor a 'predictor' of time to menopause. AMH when coupled with age and other markers provide accurate forecasts for when menopause is likely.