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Fertility matters august 09 pcosHealth Professionals Newsletter August 2009
Polycycstic Ovarian Syndrome
3. Raised blood pressure an effect that is proportional to insulin levels.
4. Potentially increased endometrial cancer risk mediated via a direct effect on the lining of the womb, but as yet unproven.
5. Hyperandrogenism (raised male sex hormone levels), primarily by acting on ovarian insulin receptors increasing ovarian androgen (male sex hormone) production in response to pituitary hormone stimulation. It is possible for a patient to have hyperandrogenism with insulin resistance and hyperinsulinemia.
These effects are exaggerated by obesity but not all hyperinsulinemic, Obesity exacerbates the problems associated with PCOS by: 1. Raising androgens (by conversion of ASD (a week androgen) to oestrone (a Chronic Anovulation
weak oestrogen)2. Raising IR (as discussed above), and 3. Reducing Sex Hormone Binding Globulin (a carrier protein found in the blood stream that binds and inactivates sex hormones) and so raising free testosterone (a strong androgen) and oestradiol (a strong oestrogen).
Central abdominal fat is more metabolically active than other fat stores. As a result a waist measurement of >90cm is predictive of abnormal endocrine and PCOS is a condition that effects about 5 - 10% of
metabolic function and increase cardiovascular risk.
Caucasian women of reproductive age and about
Weight loss of as little as 5% of starting weight has been shown to reduce
hyperinsulinemia and hyperandrogenism and may cause a resumption of
20 - 30% of infertility patients.
Diet and PCOS
This diagram highlights how the various clinical components that make up For some reason the combination of diet and PCOS is not well studied. There are PCOS interact with each other and produce the health problems associated very few published clinical trials into the effect of different diets on PCOS and those studies that are reported are on small numbers of patients. All these clinical aspects to PCOS raise the question “What are we treating?” Published studies have looked at the effects of: Two definitions of PCOS are useful to clarify this: 1) A European (the European Society of Human Reproduction and • varying polyunsaturated fatty acid content, Endocrinology) and American (the American Society of Reproductive • a low carbohydrate diet vs a monounsaturated fat rich diet and, Medicine) definition: A disease of ovarian dysfunction whose main features • a high protein vs high carbohydrate diet.
are raised male sex hormone levels and a polycystic ovarian appearance The only significant findings were that low carbohydrate diets reduced fasting insulin and free testosterone levels (after 16 days), and a diet high in protein This definition has been very useful to make a clear diagnostic basis for reduced glucose levels after meals which could be expected to reduce circulating research, but it doesn't focus on the patient's complaints and is misleading in that it suggests a single underlying cause and disease process, which hasn't Pending further evidence it seems that recommending a calorie restricted,
low carbohydrate, high protein diet is appropriate.
For practical reasons it is therefore more helpful to think of PCOS as;
2) A clinical syndrome characterized by an unexplained, long term abnormality of ovulation associated with a spectrum of associated clinical conditions. This definition highlights 2 key points, firstly it excludes other recognized hormonal causes of the same clinical presentation (such as other hormonal or glandular problems) and secondly, it highlights the syndromic nature of PCOS The good news is that whilst PCOS represents the vicious cycle shown
above, with one component of the clinical syndrome acting to reinforce the
others, breaking that cycle at one point will tend to have beneficial effect all
Hyperinsulinemia, or high blood insulin levels is caused by “insulin resistance” around. The bad news is that the treatment will have to be maintained long
(IR). This is a term that describes the inability of insulin to exert its biological term as the opposite is also true. Allowing the cycle to reform will bring a
effects at a cellular level. This is caused in turn by an insensitivity of cells to return of the full clinical manifestations of the condition.
insulin that is believed to be caused by a problem with the insulin receptors on cells. In PCOS patients the resulting elevated insulin levels are aggravated by Treatment
reduced insulin clearance from the blood by the liver and increased sensitivity Overall the advice has to be for a lifestyle modification and the recognition
of the pancreas to glucose, causing increased insulin production.
that this is a lifelong problem with women aiming at an ideal weight
Of note is the fact that obesity is not regarded as a cause of IR. It worsens equating to a BMI of 27. This correlates well with reduced insulin and
rather than causes it, as evidenced by the fact that IR is found in thin PCOS androgen levels as well as a return to normal menstrual function.
The Combined Oral Contraceptive Pill (OCP).
The OCP is the logical treatment for women not wanting to conceive. Acting
The clinical effects of the hyperinsulinemia are:
centrally to reduce pituitary hormone release it reduces ovarian androgen 1. Increased cardiovascular risk related to: lipid changes (raised triglyceride production by reducing thecal (the ovarian source of androgens) stimulation. It and reduces HDL cholesterol), increased markers for intravascular also raises sex hormone binding globulin (SHBG) levels thereby binding both inflammatory response which is associated with the development of circulating androgens and oestradiol and reducing the amount of active (free or unbound) hormone. This improves both short and long term manifestations of 2. The stimulation of fat deposition and its accumulation and the inhibition of PCOS. In terms of insulin resistance, the OCP does not improve it, but doesn't Level 26, Westfield Tower 1, 520 Oxford Street Bondi Junction 2022 Ph: 02 9389 1177 Fax: 02 9387 8580 Email: firstname.lastname@example.org
Which OCP? If hirsutism is a problem in the past, Dianne-35 for thee cycles is
Clomid produces ovulation rates in PCOS patients of up to 70%, is well tolerated effective for its immediate anti-androgen effect, and has long been the first and has few side effects. The more commonly reported adverse effects are hot choice. Yasmin however, is a newer OCP that has Drospirenone as its flashes and breast tenderness. However, with unmonitored use the multiple progestin component which is as effective in this capacity and also has useful diuretic and antihypertensive effects. It is also a 30mcg (ethinyl oestrodiol) pill Those NICE guidelines found a combination of Clomid and Metformin was better and therefore has fewer oestrogenic side effects. After three months a change than Clomid alone for ovulation giving an approximately 4.5 fold increased to either Levlen ED or Marvelon is recommended because Dianne-35 has a 4 chance of ovulation which is a similar chance as seen with injected fertility drugs, fold increased risk of venous thrombosis associated with it when compared to but it does not increase the overall pregnancy rate compared with Clomid alone. other OCPs due to its higher oestrogen content and Levlen ED is significantly Even in this context the significant side effects associated with Metformin reduce cheaper and therefore more likely to be taken long term. If hirsutism treatment and contraception are not required, and lipid profiles are at normal female Therefore Clomid is first line therapy starting with one tablet for 5 days on the 2nd levels, either cyclic Provera 10mg from 1st to 14th of each month or a Mirena to the 5th day after the onset of a spontaneous or induced period.
IUS are good options.
Metformin acts to reduce insulin resistance and hence fasting insulin levels by: Polycystic ovarian syndrome poses significant for both the patients who suffer a. Decreasing hepatic glucose production ( its main effect) and from it and the doctors who treat it. However, by focusing on the aims of therapy b. Increasing peripheral tissue sensitivity to insulin.
with a combination of lifestyle modifications and medicinal therapeutic In PCOS women its effects are controversial and difficult to separate from measures real improvements in both fertility and long term health outcomes can weight loss. However on balance Metformin is thought to reduce basal LH levels and hyperandrogenism (free testosterone levels) and to reduce insulin induced cardiovascular risk giving an expected but as yet unproven benefit to longer term treatment.
Metformin is thought to be ineffective in producing weight loss, however, it may reduce abdominal fat. A recently published multi-center RCT looking at the Fertility East IVF Clinic and Laboratories
effect of lifestyle modification and Metformin in obese PCOS patients found no improvement in weight loss. The trial took 10 years to complete and the Day Surgery
lifestyle change involved a reduced calorie, (reduced by 500 Kcals/day) high carbohydrate, low fat diet (50% carbohydrates, 10% fat), which seems again to support low carbohydrate diets in these patients. Due to the beneficial effects of Metformin it sounds like the ideal treatment however, it has the following disadvantages:1. It requires a 3 times a day dose that is poor for compliance as are its abdominal side effects, which stop about 20% of women from taking it. 2. There is a risk of lactic acidosis, a potentially serious medical condition that requires the initial monitoring of renal and hepatic function. 3. It is contraindicated in pregnancy as it freely crossed the placenta, however this is slowly being challenged as it seems to be both safe and efficacious in pregnancies complicated by Gestational Diabetes Mellitus.
As Metformin may need to be taken long-term, these disadvantages pose a significant challenge for patient compliance.
02 9389 1177
Many trials have shown that Metformin alone can make PCOS patients
ovulate. It will restore ovulation in about 40% of non-ovulatory PCOS women.
It may also increase the sensitivity of women to other fertility drugs and so
increase their effectiveness, however recent large trials suggest this is not the
A systematic review of clinical trials looking at the effectiveness of Metformin
as a fertility treatment done in 2003 found it to be an effective fertility treatment
recommending its use as an adjuvant to lifestyle changes. When compared to
placebo, PCOS patients were four times more likely to ovulate and it was also
found it to be effective in both obese and lean women. This recommendation
was endorsed by the NICE guidelines for Fertility assessment and treatment for people with fertility problems. NICE being the National institute for Clinical Pathways to Parenthood: Dr Joel Bernstein
Suite 502, Harley Place, 251 Oxford Street, Bondi Junction 2022. Therefore Metformin has a prominent place in treatment but remains a hard sell due to its side effects. Furthermore, because most women want immediate Ph: 9386 1315 www.pathways-to-parenthood.com.au results and other fertility treatments have a greater likelihood of producing The Conception Zone: Dr Julie Lukic
ovulation, other OI methods are preferred. Suite 901, 3 Waverley Street, Bondi Junction 2022. Ph: 8362 2200 www.theconceptionzone.com.au Clomid (Clomiphene Citrate) is an anti-oestrogen, non-steroidal, diethylstilbestrol derivative like Tamoxifen, made in 1957 and licensed in the US for use in 1967. It acts by binding to receptors in the brain causing their Goals for Women: Dr Polly Peres, Dr Jenny Cook
depletion which increases pituitary hormone secretion. In essence it tricks the 16th Floor, Suite 1605, Westfield Tower 2, 101 Grafton Street, brain into thinking there is less oestrogen circulating than there actually is, Bondi Junction 2022 Ph: 1300 88 6009 www.goalsforwomen.com.au causing increased pituitary FSH release stimulating ovulation.
Level 26, Westfield Tower 1, 520 Oxford Street Bondi Junction 2022 Ph: 02 9389 1177 Fax: 02 9387 8580 Email: email@example.com