Pharmacy update – Bad hair day?
7 June 2003
Chemist & Druggist
(c) 2003 CMP Information Ltd.
Women who complain of being spotty, overweight and hairy may be suffering from a common metabolic disorder that could affect fertility and have long-term health consequences, not just vanity. Vanessa Sherwood looks at polycystic ovarian syndrome
Objectives l To be aware of the symptoms of PCOS l To understand the possible causes of the syndrome l To understand how PCOS is diagnosed l To appreciate the importance of lifestyle advice l To be aware of drug treatments for PCOS
Polycystic ovarian syndrome is a multi-factorial condition, affecting women of reproductive age. It is the most common cause of anovulatory infertility.1
However, as celebrity mothers such as Victoria Beckham and Jools Oliver, both sufferers, have each had two children, the effects of PCOS on fertility are not necessarily insurmountable.
PCOS may also be known as Stein-Leventhal syndrome, sclerocystic ovaries or polycystic ovarian disease.
Normally, an ovary consists of fibrous tissue containing immature, preformed follicles. Each follicle contains an oocyte, a precursor of an ovum, surrounded by follicular cells. About half a million follicles are formed during foetal life and approximately 500 of them mature during adult life. The remainder, usually undeveloped follicles, degenerate and all are lost at the onset of the menopause.
The growth and release of the ovum is controlled by follicle stimulating hormone (FSH) and luteinising hormone (LH) respectively.
In polycystic ovarian syndrome, some follicles develop to a mature stage but do not rupture to release the ovum and this, in turn, prevents the normal hormone cycle being initiated. These mature but unruptured follicles congregate on the outer surface of the ovaries and are described as cysts.
PCOS sufferers may have 10 or more follicle cysts in each ovary.
Ultrasound findings often include multicystic ovaries with the follicle cysts lining up on the periphery of the ovary. The ovary then secretes higher levels of testosterone and oestrogen, resulting in the most common presenting symptoms: irregular or missing periods, infertility, excess body hair growth, often obesity, insulin resistance or diabetes and hypertension, male-pattern baldness and abnormal serum lipid concentrations.
Because of the problems with insulin resistance and abnormal lipids, women with PCOS are at a higher risk of diabetes and cardiac problems than women of the same age without the syndrome.
How common is PCOS?
The estimated prevalence depends on the symptoms used to define PCOS but is in the range of 5-10 per cent of pre-menopausal women. Definition and diagnosis of PCOS varies between countries. In the USA ultrasound of the ovaries is not required to make the diagnosis – clinical features such as hirsutism, male-pattern baldness and acne along with ovulatory dysfunction are all that is required.2 In the UK ultrasound examination of the ovaries is used to confirm a diagnosis.
What causes PCOS?
As it is such a complex disorder with many hormonal factors playing a part there have been many theories about the cause of PCOS.
Around 40 per cent of sufferers have raised levels of LH and 30 per cent have raised levels of testosterone.
LH stimulates the ovary to produce testosterone and consistently raised levels of LH can prevent ovulation.
There is some debate as to whether the insulin resistance associated with PCOS is a cause or effect of the syndrome. Recent evidence has suggested that the principal underlying disorder may be insulin resistance with the resultant raised serum insulin concentrations stimulating excess ovarian androgen production.3
Excess circulating insulin also reduces the production of proteins that bind sex hormones, increasing the free testosterone levels.
A high body mass index could also be a cause or effect. Increased weight can lead to increased serum insulin concentrations and, as described above, increased free testosterone levels.
There may be a genetic factor but this remains controversial.
PCOS is a complex, `chicken and egg’ hormonal syndrome. As such, there is no cure but the emphasis lies in treating the symptoms.
Women present with the classic symptoms of PCOS as described previously rather than with the syndrome. Diagnosis can be difficult because of the varying definitions of “normal”. Excess body hair for one woman may be normal for another.
Typical investigations include an ultrasound of the ovaries and blood tests to measure hormone levels. Further examinations with CAT scan, MRI, biopsy or laparoscopy for diagnosis are usually unnecessary.
Only 50 per cent of women with classic polycystic ovaries on examination also have hirsutism and anovulation. Characteristic hormone levels for PCOS would be testosterone between 2.6-4.8nmol/l (normal 0.7-2.8nmol/l) and LH above 10IU/l.
Women who present only with hirsutism should just have testosterone levels measured. Hair growth in PCOS is usually gradual but women who present with sudden hair growth and serum testosterone above 4.8nmol/l should be investigated as this could indicate adrenal hyperplasia and/or an androgen-secreting tumour.
In women with menstrual disturbances measurement of FSH, prolactin and thyroid hormones in addition to LH are useful to rule out any other reasons for menstrual disturbance.
Concentrations of FSH, TSH and prolactin are normal in women with PCOS but the increased level of LH alters the LH to FSH ratio.
Fasting serum glucose should be measured in women with a body mass index above 27. Lean and obese women with PCOS can show decreased insulin sensitivity but insulin resistance is most marked in those with a BMI greater than 27.
There is decreased sensitivity to insulin in peripheral tissues (muscle and adipose tissue) but not – unlike type 2 diabetes – hepatic resistance.
Insulin resistance is uncommon in women with hirsutism, hyperandrogenaemia and polycystic ovaries who have regular menstrual cycles; they have insulin sensitivity similar to those in weight matched normal subjects.
It is unlikely that anovulation is the cause of insulin resistance – it is most likely that increased serum insulin concentration and insulin resistance contribute to anovulation.
GPs should refer patients to specialists when infertility is the presenting problem or when the diagnosis is in doubt.
Drug, non-drug and complementary: restoring ovulation and decreasing the testosterone levels are usually the main goals of therapy but weight loss and the prevention of endometrial cancer are also important considerations.
However, the symptoms the woman finds most distressing or upsetting are likely to be treated first, and this will probably depend on her age. A young woman in her late teens or early 20s may be more concerned with acne and hirsutism, whereas an older woman in her 30s wishing to start a family may be more concerned about her irregular periods and inability to conceive. The treatment of each symptom will be considered individually.
Irregular periods: the combined oral contraceptive pill can be used to regulate periods. It reduces free testosterone levels by decreasing androgen secretion and increasing levels of sex hormone-binding globulin. However, it can exacerbate insulin resistance and is unsuitable for obese patients.
By promoting regular periods combined oral contraceptives can reduce the risk of endometrial hyperplasia. The progestogen used should be one with low androgenic potency such as norgestimate (Cilest) and desogestrel (Marvelon and Mercilon). Norgestrel and levonorgestrel are not recommended.4
Progestogens alone are used where the woman’s primary concern is restoration of regular periods, and not the treatment of infertility or hirsutism. Medroxyprogesterone acetate, 5-10mg daily for 10-12 days every month, or every other month, will prevent the development of endometrial hyperplasia and, in the long term, protect against endometrial cancer.
Hirsutism: can be reduced by the use of anti-androgens such as cyproterone acetate. In combination with ethinyloestradiol (for example, Dianette) it may regulate the menstrual cycle and provide effective contraception. In the USA spironolactone (100mg once or twice daily) is frequently used to treat hirsutism. The mode of action of both drugs is inhibiting the binding of dihydrotestosterone to its receptor at the hair follicle. Beneficial effects can be seen after three months but the hair growth will resume if treatment is stopped.
Flutamide and finasteride have also been used as anti-androgens, again mainly in the USA. Flutamide has a similar action to cyproterone and spironolactone, while finasteride inhibits the activity of the enzyme 5-alpha reductase. This converts testosterone to the more potent dihydrotestosterone.
Side effects of anti-androgens include menstrual irregularity, hyperkalaemia, dizziness and gastrointestinal effects. All are contraindicated in women trying to conceive.
While waiting for the drug treatment to become effective women can use cosmetic methods of hair removal such as waxing or electrolysis. Neither is available on the NHS and the cost of the latter may be prohibitive for some women.
Acne: can be helped by the use of anti-androgens, but may take three to six months. Dianette is licensed for the treatment of acne but in the absence of any improvement usual treatments for acne are used, such as topical or systemic antibiotics or isotretinoin.
Male-pattern baldness: this symptom may take longer to respond to anti-androgenic treatment or may not respond at all. Again, symptoms will recur when treatment is withdrawn.
Infertility: Clomifene citrate is the drug of choice in PCOS but is associated with an increased risk of multiple pregnancy. It works by inhibiting the oestrogen-mediated negative feedback loop at the hypothalamus, enhancing the secretion of FSH.
In the treatment of hyperandrogenic, anovulatory women clomifene has been reported to increase the frequency of ovulatory cycles by 80 per cent and the rate of pregnancy by 67 per cent. Treatment is less likely to be successful in women who are overweight. It should not be used for more than six months because of the potential increased risk of ovarian cancer.
Those women who do not respond to clomifene usually respond to exogenous gonadotrophins but this requires intensvie monitoring by a specialist to reduce the risk of multiple conceptions.
Obesity: weight loss can restore ovulation and women with PCOS should be offered lifestyle advice incorporating diet and exercise. Obesity can also aggravate insulin resistance and therefore weight loss is important in controlling two features of the syndrome. However, women with PCOS find it extremely difficult to lose weight but it is not known why.
Insulin resistance: as recent evidence has suggested that insulin resistance may be a cause and not an effect of PCOS, then treating insulin resistance has the potential to be the most appropriate action.
Metformin has been the most commonly used drug in small trials but it is still not licensed for the treatment of PCOS. Trials have shown that metformin (1,500 -1,700mg/day):
* reduces concentration of fasting serum insulin, androgens and LH
* increases levels of sex hormone binding globulin, reducing free testosterone
* restores regular menstrual cycles and ovulation.
Some people have also lost weight despite continuing with a normal diet and lifestyle. Metformin should only be used in women with normal renal and hepatic function.
The use of metformin and clomifene together may have a synergistic effect. In a small trial of 61 women, 90 per cent of those receiving both drugs ovulated compared with 8 per cent of those who just took clomifene plus placebo.
Troglitazone, a thiazolidinedione, also had a beneficial effect on insulin resistance and circulating androgen levels but it was withdrawn in 1997 because of hepatotoxicity.
The newer thiazolidinediones, such as rosiglitazone and pioglitazone have reduced hepatotoxicity but no trials have yet been carried out for PCOS. GlaxoSmithKline, manufacturer of rosiglitazone (Avandia) says that it has no plans to run any trials of its use as a treatment for PCOS. However, the company was aware of one published case where a 25 year old woman with PCOS was treated with rosiglitazone 4mg daily for five months.5 Rosiglitazone improved insulin sensitivity and lowered serum-free testosterone and resulted in spontaneous ovulation and conception.
Complementary therapies: Saw palmetto 320mg daily may be effective in reducing the effect of androgens as it works in a similar way to finasteride – blocking the efficacy of 5-alpha reductase on receptors in benign prostatic hyperplasia. However, there is no evidence to support its use in PCOS.
Surgery is a last resort. In women who have tried all other medications ovarian diathermy “drilling” or electrocautery by laparoscopy may induce ovulation, by reducing ovarian steroid production. Formerly ovarian wedge resection was used – a small “wedge” or section of ovary was removed under general anaesthetic. All surgical treatments can cause adhesions, which worsen infertility.
Authors of a study in the BMJ have said there is an urgent need for randomised, placebo-controlled trials to assess the potential benefits of treatments such as metformin. Dr Zoe Hopkins, a clinical research fellow at the Glasgow Royal Infirmary University NHS Trust said: “Treatments targeting the key factor in the disorder may not only resolve the gynaecological problems the syndrome presents but may also reduce the risk of vascular disease in later life.”
Women with a diagnosis of PCOS should be counselled on the importance of losing weight (if necessary) and maintaining a BMI in the normal range (20-25), by eating a healthy diet and exercising. The importance of this for their long-term health prospects, not just immediate effects, should be explained.
1. Frank, S. Polycystic ovary syndrome. N Engl J Med 1995; 333: 853-861.
2. Tackling polycystic ovarian syndrome. Drug and Therapeutics Bulletin 2001; Vol 39 No 1.
3. Hopkinson, ZEC, Sattar N, Fleming, R, and Greer, I A:
Polycystic ovarian syndrome: the metabolic syndrome comes to gynaecology; BMJ 1998; 317: 329-332.
4. Patel, SR and Korytkowski, M T: Treating polycystic ovarian syndrome: today’s approach. Women’s Health in Primary Care 2000, Vol 3, No 2.
5. Cataldo, NA et al: Fertility and Sterility 2001, 76 (5); 1057-1059.
For more information:
Patient support group: http://www.verity-pcos.org.uk/
Z Binor/Custom Medical Stock Photo/Science Photo Library
PCOS may be used to cover the following conditions:
* traditional PCOS – anovulatory, increased androgens, no insulin resistance
* endocrine syndrome X – anovulatory, increased androgens, insulin resistance or type 2 diabetes
* non-traditional PCOS – anovulatory, normal androgens, obese, insulin resistance or type 2 diabetes or
* ovulatory, increased androgens, mild insulin resistance
* idiopathic hirsutism – ovulatory, increased androgens, no insulin resistance.
Because of anovulation, and risk of irregular and heavy menstrual bleeding, women are at risk of endometrial hyperplasia and even endometrial cancer.
PCOS sufferers exhibit raised triglyceride and decreased high-density lipoprotein concentrations, both strongly linked with cardiovascular disease. Discrepancies in lipid levels between sufferers and non-sufferers matched for weight and age are evident at an early age.
Retrospective studies have also shown increased evidence of cardiac disease. In one study, women who had been treated for PCOS 20-30 years earlier were four times more likely to have hypertension and seven times more likely to have diabetes than controls.
1. Do you have any patients who have polycystic ovarian syndrome? How many? Do any have children? Did they have multiple births? Was fertility treatment required by these women? If so, do you know what was used?
2. Think about these women. What are their symptoms? Would you recognise them by their appearance? What drugs were or are being prescribed?
3. Irregular periods are not uncommon. In your practice workbook list some other likely causes. Do you know of any of your patients who have irregular periods which are not the result of polycystic ovarian syndrome? Are they receiving drug treatment and if so which drug(s)?
4. Are there other uses of saw palmetto? Try to find out if there are other alternative medicine drug therapies or complimentary medicine treatments for the symptoms of polycystic ovarian syndrome.