Polycystic ovary syndrome (PCOS) and fertility

What is polycystic ovary syndrome?

Polycystic (literally, many cysts) ovary syndrome (PCOS or PCO) is a complex condition that affects the ovaries (the organs in a woman's body that produce eggs).

It's complex because there are some very typical appearances in the ovaries that give the condition its name. But these are not always present and do not have to be present.

In PCOS, the ovaries are generally bigger than average. The outer surface of the ovary has an abnormally large number of small follicles (the sac of fluid that grows around the egg under the influence of stimulating hormones from the brain).

There are also characteristic changes in the appearance of the ovaries on anultrasound scan.

The ovaries are polycystic, with many small follicles scattered under the surface of the ovary (usually more than 10 or 15 in each ovary) and almost none in the middle of the ovary. These follicles are all small and immature, and generally do not exceed 10mm in size and rarely, if ever, grow to maturity and ovulate.

In PCOS, these follicles remain immature, never growing to full development or ovulating to produce an egg capable of being fertilised. For the woman, this means that she rarely ovulates (releases an egg) and so is less fertile. In addition, she doesn't have regular periods and may go for many weeks without a period. Other features of the condition are excess weight and body hair.

The condition is relatively common among infertile women. If affects up to 10 per cent of all women between the ages of 15 and 50 and is particularly common among women with ovulation problems (an incidence of about 75 per cent).

In the general population, around 25 per cent of women will have polycystic ovaries seen on an ultrasound examination. But most have no other symptoms or signs of PCOS and have no health problems. The ultrasound appearance is also found in up to 14 per cent of women on the oral contraceptive pill.

What causes PCOS?

While it's not certain if women are born with this condition, PCOS seems to run in families. This means that something that induces the condition is inheritable, and therefore influenced by one or more genes.

Ongoing research is trying to clarify whether there's a clearly identifiable gene for PCOS. Several different genes have been implicated in the condition – none have been definitely implicated as being the prime cause. Perhaps this role of several genes, and not one in particular, is what lies behind the way in which the condition is expressed so differently in people.

We know that PCOS has some genetic basis, but it's unlikely that all women with one or more of these genes will develop the condition. It's more likely to develop, if there's a family history of diabetes (especially Type 2, the less severe type usually controlled by tablets) or if there's early baldness in the men in the family.

When the genetic tendency for PCOS is passed down through the man's side of the family, the men are not infertile – but they do have a tendency to become bald early in life, before the age of 30.

A number of marker proteins have also been identified in the blood of women with PCOS, further supporting the view that this is a genetically determined disorder.

Women are also more at risk if they're overweight. Maintaining weight or body mass index (BMI) below a critical threshold is probably important to determine whether some women develop the symptoms and physical features of the condition. Just how much weight (or what level of BMI) is difficult to say because it will be different for each individual.

Certainly, for patients who are considered overweight (BMI 25 to 30) or obese (with BMI greater than 30), weight loss improves the hormonal abnormalities and improves the likelihood of ovulation and therefore pregnancy.

Can PCOS be prevented?

Not being certain of the exact cause makes it difficult to answer this question fully.

If there's a genetic influence, some people are more likely to get PCOS than others. But it seems likely that you cannot alter your predisposition to PCOS.

There's no current proof of any benefit of preventative weight loss. But the best advice for overall health is to maintain a normal weight or BMI, particularly if you have strong indicators that PCOS could affect you.

These indicators include:


a tendency in the family towards Type 2 diabetes (non-insulin dependent diabetes)
the knowledge that a close relative already has PCOS
a tendency towards early baldness in the men in the family (before 30 years of age).

What are the symptoms?

The ways that PCOS shows itself include:

• absent or infrequent periods (oligomenorrhoea): a common symptom of PCOS. Periods can be as frequent as every five to six weeks, but might only occur once or twice a year, if at all
• increased facial and body hair (hirsutism): usually found under the chin, on the upper lip, forearms, lower legs and on the abdomen (usually a vertical line of hair up to the umbilicus)
• acne: usually found only on the face
• infertility: infrequent or absent periods are linked with very occasional ovulation, which significantly reduces the likelihood of conceiving
• overweight andobesity: a common finding in women with PCOS because their body cells are resistant to the sugar-control hormone insulin. This insulin resistance prevents cells using sugar in the blood normally and the sugar is stored as fat instead
• miscarriage (sometimes recurrent): one of the hormonal abnormalities in PCOS, a raised level of luteinising hormone (LH - a hormone produced by the brain that affects ovary function), seems to be linked with miscarriage. Women with raised LH have a higher miscarriage rate (65 per cent of pregnancies end in miscarriage) compared with those who have normal LH values (around 12 per cent miscarriage rate).

These symptoms are related to several internal changes, some of which can be relatively easier understood in the light of the hormone abnormalities that are frequently found.

These include:

• raised luteinising hormone (LH) in the early part of the menstrual cycle
• raised androgens (male hormones usually found in women in tiny amounts)
• lower amounts of the blood protein that carries all sex hormones (sex-hormone-binding globulin)
• a small increase in the amount of insulin and cellular resistance to its actions
• raised levels of anti-Mullerian hormone, when compared with women with normal regular cycles (this may become a more useful and accurate test than checking LH or the LH to FSH ratio).

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

How is PCOS diagnosed?

The diagnosis is based on the patient's symptoms and physical appearance.

If the diagnosis seems likely, because the patient's history contains many of the symptoms described already, certain investigations are done to provide confirmatory evidence or to indicate another cause for the symptoms.

These include:

blood tests such as:

• female sex hormones (particular time points in the cycle are important for some of these)
• male sex hormones
• sex-hormone-binding globulin
• glucose
• thyroid function tests
• other hormones, eg prolactin.

ultrasound examination.

Your own GP can do the initial blood investigations, ensuring they are carried out at the correct time of the cycle if appropriate. Your GP may be able to arrange an ultrasound scan.

Once the diagnosis is made, nothing more needs to be done for some women, eg if their fertility is not an issue, if their weight is within normal limits, and if they do not have excess body hair.

If any of the symptoms are an issue – further advice and treatment, and possibly specialist referral, is needed.

What else could it be?

The other conditions likely to cause abnormal periods include raised levels of prolactin and of thyroid stimulating hormone (TSH). Both these hormones are produced from a particular part of the brain, the anterior pituitary.

Raised prolactin levels can occur together with headaches and some disturbances of vision, whereas raised TSH levels indicate low thyroid hormones (hypothyroidism). Both these conditions lead to suppressed ovulation and infertility.

Increased hair and acne reflect an increase in male hormones (androgens) in the blood. Other conditions can cause such an increase.

Rarely, adrenal disorders or tumours cause increased androgens. In these conditions: hirsutism usually develops quite rapidly, previously normal periods may also stop and, occasionally, muscle weakness occurs.

Loss of, or changes in, female aspects of body shape and appearance (secondary sexual characteristics), especially reduction in breast size, may also occur.

As the androgen excess progresses, the voice can deepen and the clitoris can increase in size (clitoromegaly). If these serious medical disorders are present, the male hormone levels will be considerably increased, way above those found in PCOS, and specialist treatment should be arranged.

What can you do for PCOS?

There are several things that an individual can do if they have a tendency towards developing some or all of the elements of PCOS. Much of this involves lifestyle changes to ensure that your weight is kept within normal limits (BMI between 19 and 25).

In addition, because there is a likelihood of developing diabetes in later life and a slightly higher risk of heart disease, low-fat and low-sugar options should be considered when making choices about what to eat or to drink.

Weight loss, or maintaining weight below a certain level, will have the short-term benefit of increasing the likelihood of successful treatment and the long-term benefits of reducing the risk of diabetes and heart disease.

Weight loss is effective in reducing male hormone levels, increasing the likelihood of ovulation and getting pregnant.

Using medications to lose weight may be effective, and orlistat is probably the most effective of these. Metformin on the other hand is probably not effective in helping to lose weight though evidence on this is conflicting.

It's interesting that despite all the research into PCOS, the exact relationship between the condition and weight gain (or loss) is unclear. But being overweight, and especially increased abdominal fat, seems to be a strong predictor of having other hormonal problems – such as raised male hormones and tendencies to having diabetes.

What can your doctor do?

Your family doctor will be able to provide many of the drug treatments available (although these are probably best taken in consultation with a specialist). Treatments aim to improve several aspects of PCOS, including:

• fertility, via the stimulation of ovulation
• reduction of the insulin resistance
• reduction of the increased hair.

Treatments

The range of treatments available and their application are listed in Tables 1 and 2.

Table 1 deals with the treatments for improving fertility in women with PCOS (Homberg, 1998; Pirwany et al, 1999; Farquhar et al, 2000; Hughes et al, 2000a; Hughes et al, 2000b; Hughes et al, 2000c).

Table 2 deals with the treatments for other features of PCOS including hirsutism, irregular or absent periods and obesity. The evidence in favour of using of these medications to improve symptoms is not strong and reviewed elsewhere in detail.

Table 1: Treatments to improve fertility in women with polycystic ovary syndrome
Drug and mode of action	Benefits	Risks	Effects on life quality
Clomifene (eg Clomid): mild stimulant of ovarian function.	Effective method to achieve ovulation.	1. Very low risk of ovarian hyperstimulation syndrome.	1. Simple easy method of treatment with tablets to be taken by mouth, for five days each month.
		2. Possible risk of multiple pregnancy if several mature follicles develop.	2. Minimal effects while taking tablets, though some develop headaches.
		3. Increased risk of ovarian tumours in women having more than 12 cycles of treatment.	3. Obvious benefit if pregnancy ensues (pregnancy also lowers the increased risk of ovarian tumour back to that of the normal population).
Gonadotrophin injections: direct stimulation of the ovarian follicles to grow.	Ovulation rates of over 90 per cent in most women and pregnancy rates of 20 to 25 per cent per cycle.	1. Ovarian hyperstimulation syndrome.	1. Require daily injections of hMG or FSH derived from urine or recombinant FSH.
		2. Multiple pregnancy if many mature follicles develop.	2. Several studies suggest the benefits of taking a second drug in conjunction. This should suppress LH and improves the chances of an ongoing pregnancy.
Metformin (eg Glucophage): many actions – eg reduction of male steroid production by the ovaries.	Early reports suggested ovulation rates in up to 90 per cent of cycles. More recent reviews suggest that it does not improve success at IVF but reduces the risk of overstimulation of ovaries with IVF.	No significant associated risk.	Considerable gastrointestinal upset reported – particularly diarrhoea – which is somewhat improved by reducing the daily dose.
Gonadotrophin releasing hormone agonists: stimulate the release of natural sex hormones from the brain.	Lowers LH concentrations and reduces the likelihood of miscarriage.	Needs to be used in conjunction with FSH injections and therefore all the above risks also are present. GnRH agonists themselves have little risk in short-term use.
Aromatase inhibitors (letrozole, anastrozole).	May be useful in women who do not respond to clomifene.	Maybe associated with fewer follicles and pregnancies.

Table 2: Treatments for other features of polycystic ovary syndrome
PCOS feature	Available treatment	Comments
Raised androgen (male sex hormone) level	Metformin (eg Glucophage)	1. Metformin reduces the abnormal findings of raised androgens and decreased sex-hormone binding protein in the blood. But it can cause considerable gastrointestinal upset – particularly diarrhoea – that's somewhat improved by reducing the daily dose.
Irregular periods	Metformin	1. Return of periods in 90 to 95 per cent of women.
Obesity	Metformin and Orlistat (Xenical)	1. Several studies have examined the effect on weight loss; the majority support its effectiveness.
		2. Orlistat is recommended by NICE in the UK for adults who have lost at least 2.5 kg by diet and increased activity in the month prior to their first prescription and are obese.
Hirsutism	Combined oral contraceptives, especially containing the anti-androgen cyproterone acetate (eg Dianette).	1. These increase the levels of the sex hormone carrier in the blood, leaving less androgen free to cause hirsutism.
		2. It may take six months before any noticeable improvement occurs and two to three years to achieve the maximum benefit from anti-androgens because of the length of the growth-cycle of hair.
Hirsutism	Finasteride and flutamide	1. Finasteride reduces the amount of hair by preventing androgen getting into cells. It can cause headache and depression, and contraception is essential to avoid accidental exposure to a foetus. Flutamide is equally effective with finasteride.
Hirsutism	Metformin	Appears to bring about a reduction in hirsutism when compared with other drugs, and particularly, it is more effective than Dianette.
Cancer of the uterus	Progestogens, medroxyprogesterone acetate	General acceptance that this stops endometrium (womb lining) from developing, counteracts any tendency to cell abnormalities and cancer.

Adverse effects of having PCOS

It's likely that there are different stages of the disease throughout life.

Younger women tend to have difficulties with their periods, whereas older women have other problems – such as diabetes and hypertension (high blood pressure), though their period patterns tend to become more regular.

Women with PCOS have an increased risk of strokes and heart attacks – although the likelihood of dying because of these conditions isn't increased.

Women with PCOS have an increased risk of cancer of the uterus, particularly if they have infrequent or absent periods (up to three times). They also appear to have a increased risk of cancer of the ovaries (up to two times).

The increased risk of cancer of the uterus is thought to be due to certain hormonal abnormalities that result in continuous stimulation of the lining of the womb by oestrogen. However, the mild increase in insulin found in these women may also have negative effects.

There appears to be no increased risk of breast cancer in women with PCOS. The consensus is that it's sensible to advise women with PCOS and absent or very infrequent periods to take occasional progestogen therapy to 'oppose' the oestrogen and minimise the risk of cancer of the uterus.

Non-drug treatments

Ovarian diathermy (surgery that uses heat to alter ovarian function) is thought to reduce the amount of androgen secreting tissue in the ovaries, leading to resumption of ovulation in up to 80 per cent of women.

The risks include those of having a laparoscopy and a theoretical risk of ovarian damage from the diathermy. The benefits include resumption of ovulation in a simple manner, with effects lasting six to nine months.

There's a range of non-drug treatments available for hirsutism. Once a serious increase in male hormone levels has been excluded, then local cosmetic options can safely be considered. These include:

• bleaching
• depilatory preparations
• waxing
• plucking
• laser hair removal
• electrolysis
• shaving.

Each is usually effective, but expert advice should be taken because each method has its own problems.

Bleaching and depilatory preparations can occasionally cause a local allergic reaction.

Waxing and plucking often break the hair shaft rather than actually remove it from the hair follicle and, therefore, should be considered to be little more effective than shaving.

Electrolysis and laser hair removal usually give the most prolonged action but both are expensive and cannot tackle large areas of the skin. Electrolysis is painful and laser removal may not be permanent.

Damage to skin or follicles can also occur with either. Waxing, plucking and shaving can lead to inflammation and infection of hair follicles, requiring topical antibiotic creams.

Sugaring is less likely to provoke this result than waxing. Best results will be obtained from shaving if hypoallergenic shaving soaps and razors are used. There is no evidence that plucking, waxing or shaving will encourage increased hair growth.

source:  netdoctor.co.uk