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Diagnosing and treating disorders of ovulation

Common causes of ovulatory problems are generally amenable to treatment ­ Dr David Cahill and Dr Valentine Akande describe how

The term ovulation implies the release of an egg from its growing fluid-filled follicle in the ovary. The egg also needs to be fully mature. The maturation process is implicitly and directly linked with the maturity of the growing follicle. A follicle is the sac of fluid that grows around the egg under the influence of stimulating hormones from the brain.

For this reason the state of maturity of the follicle is often used as an indicator for the maturity of the egg. Follicle maturity is shown by the amount of hormones produced: oestrogen before ovulation and progesterone afterwards. It is easier to measure progesterone, when it is at its peak about one week after ovulation.

In response to progesterone, the body temperature rises and temperature charting each day has been the traditional test of ovulation ­ but it may be difficult to interpret.

Additionally, only a little rise in progesterone brings about the full rise in temperature that occurs after ovulation. The temperature reaches a plateau very quickly, but progesterone keeps on rising to much higher levels provided there was a fully mature

follicle. A smaller progesterone rise shows the follicle was not mature enough even though sufficient to shift the temperature. Temperature rises are also subject to a number of other interfering factors such as viral illness or early or late rising.

The timing of ovulation, and therefore the progesterone peak, is related to the following menstrual period, not to the last menstrual period. The normal time after ovulation to the following menstruation is about two weeks, therefore progesterone measurement must be done about seven days before the expected menstrual period. The traditional timing of the progesterone measurement on day 21 (from the start of the menstrual cycle) is based on the average 28-day cycle but is way out in a 35-day cycle (when it should be done on day 28).

Our practice is to ask women to contact us by telephone once their period comes so that the relationship between the blood sample date and the first day of the period can be established, ensuring that the test is a valid one.

The routine measurement of progesterone in women who have regular monthly menstrual cycles is of questionable value. Even if the levels are low in the first one or two cycles they will usually turn out to be normal in most cycles. Our experience in sequential cycle measurements suggests at least one cycle in six in an otherwise healthy normal woman will be dysfunctional. Variation in the quality of ovulation between cycles is normal, and tests on many cycles are needed to be sure of a persistent problem. Real, persistent ovulatory disorder causing infertility usually only occurs in women who have infrequent or absent menstrual periods, and they need special investigations of the cause.

Nevertheless, it is common practice to measure progesterone in two or three cycles because it is simple and seems reassuring. But remember: timing must be correct, and treatment is of no benefit unless a clearly persistent disorder is evident in many more cycles.

Problems with ovulation

Temporary or permanent failure of ovulation is indicated by absent or infrequent menstrual periods (amenorrhoea and oligomenorrhoea respectively). There are numerous distinct causes of ovulation failure, and several hormone and other investigations are required to reach an accurate diagnosis and select the right treatment. But with the exception of a premature menopause, most cases are responsive to treatment.

Diagnosing problems with ovulation

If a woman has regular cycles every 26 to 30 days and has periods that are painful and of normal flow (four to five days in duration), it is very likely that she is ovulating. Further measurements beyond serum progesterone are unlikely to move things significantly forward.

If this is not the case then it is more likely that a significant problem with ovulation is present and more extensive investigation is required and may be beneficial.

These will include blood samples for:

 · The gonadotrophins follicle stimulating hormone (FSH) and luteinising hormone (LH) during the first few days of the menstrual cycle. This test may need to be repeated in another one or two cycles because the hormone levels can vary significantly from cycle to cycle.

 · Prolactin and thyroid stimulating hormone (TSH) can be taken at any time, either with the progesterone or the gonadotrophins. As a result of these tests, one of three common problems is likely to emerge:

 · Polycystic ovary syndrome

 · Hyperprolactinaemia

 · Hypothyroidism

Other problems such as ovarian failure or failure of release of gonadotrophin releasing hormone (GnRH) are treated by oocyte donation and by means of a specialist pump therapy, neither of which will be managed in primary care.

Polycystic ovary syndrome

This is a complex condition that primarily affects the ovaries. In PCOS (or more loosely sometimes PCO) the ovaries are bigger than average, and the outer surface of the ovary is covered by a large number of small follicles.

In PCOS, these follicles remain small and immature, generally do not exceed 10mm in size and fail to develop or ovulate to produce an egg capable of being fertilised. The woman ovulates less frequently and so is less fertile. In addition, she may go for many weeks without a period. Periods can be as frequent as every five to six weeks but might only occur once or twice a year, if at all. There may be other features of the condition present such as excess weight or excess body hair.

Among infertile women the condition is relatively common. Among women with ovulation problems, PCOS is found in about 75 per cent. In the general population, around 25 per cent of women will have polycystic ovaries on ultrasound examination but many will have no other symptoms or signs of PCOS and are perfectly healthy. These women should not be told they have PCOS. Indeed, the ultrasound appearance is also found in up to 14 per cent of women on the contraceptive pill.

PCOS shows itself in a number of ways besides absent or infrequent periods. Women may of course be infertile as the infrequent or absent periods are linked with very occasional ovulation, which significantly reduces the likelihood of conceiving. Signs of excessive male hormones may be evident as increased facial and body hair hirsutism (under the chin, on the upper lip, forearms, lower legs and on the abdomen as a vertical line of hair up to the umbilicus) or acne (usually found only on the face).

They may be overweight or obese (usually designated by a BMI greater than 25 or 30 respectively). This is a common finding in women with PCOS because their body cells are resistant to insulin. Insulin resistance prevents cells using sugar in the blood normally and instead the sugar is stored as fat. Finally, sometimes women with PCOS present with miscarriage, sometimes recurrent.

These ways in which women present are related to several hormonal and ultrasound abnormalities, including:

lraised LH in the early part of the menstrual cycle

lraised androgens (testosterone)

llower amounts of sex hormone binding globulin

la small increase in the amount of insulin and cellular resistance to its actions (very difficult to measure or assess in routine clinical practice)

lcharacteristic ultrasound appearance of the ovaries on scans.

Most women with PCOS will have the ultrasound findings, while the menstrual cycle abnormalities are found in around 66 per cent of women and obesity in 40 per cent. The increase in hair and acne are found in up to 70 per cent while the hormone abnormalities are found in up to 50 per cent of women.

The treatments available for PCOS and their relative effectiveness are summarised in table 2 above.

Hyperprolactinaemia

Raised prolactin levels are sometimes found associated with irregular or (more commonly) absent periods and absence of ovulation. When present these are usually due to a small (<2mm) tumour="" that="" is="" secreting="" excess="" prolactin="" in="" the="" pituitary="" gland.="" rarely="" will="" these="" tumours="" be="" visible="" on="" mri="" scan="" or="" cause="" any="" other="" symptoms.="" if="" a="" tumour="" is="" visible="" on="" mri="" scan="" it="" often="" will="" not="" be="" the="" actively="" secreting="">

Women may present or have other symptoms on questioning such as leaking milk (galactorrhoea) or more rarely tunnel vision (bitemporal hemianopia) caused by the tumour growing and pressing on the optic nerves.

With these symptoms, and prolactin levels exceeding normal (usually >1000iu/l) and other tests being normal, effective treatment using cabergolide or bromocriptine can be started. Both are effective, but the first has fewer side-effects and is more expensive.

Within four to six weeks, prolactin levels should return to normal and the inhibition of activity, which it causes, is removed. Normal cycle activity should resume in a short time.

As well as checking visual fields for any deficiencies at the beginning of treatment, monitoring of blood levels and visual fields at yearly intervals is required in stable treated patients. Any alterations in vision should be reported immediately and acted upon and it may signify a growth in the tumour and potential for loss of vision.

Failure to do so means the tumour may require more radical intervention by surgery (trans-sphenoidal hypophysectomy) usually carried out in specialist neurosurgical centres.

Hypothyroidism

This is a subtle and more difficult diagnosis to make. The patient may not be particularly aware of the impending signs or symptoms of thyroid deficiency and may present with irregular (more commonly) or absent periods.

Again diagnosis depends on other normal results and the finding of an elevated TSH concentration in the blood. Treatment by thyroxine replacement is effective and will restore the endocrine abnormality within four to six weeks. In women presenting with hypothyroidism, it may be worth considering screening for autoimmune thyroid disease (and indeed other autoimmune disorders).

In summary, common causes of ovulatory problems are generally amenable to treatment, though this can require specialist intervention. Assessment of ovulatory function at the appropriate times of the menstrual cycle is a key element to the management of couples with infertility.

David Cahill is a consultant senior lecturer at the Centre for Reproductive Medicine, University of Bristol

Valentine Akande is a clinical lecturer at

St Michael's Hospital, University of Bristol

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