Friday, 28 September, 2007

PCOS - A Brand New Approach To Treating This Metabolic Disorder



Women with polycystic ovary syndrome who are hoping to conceive have reasons for both hope as well as concern. I hope this article will introduce you with newer treatment options and educate you to choose well prior to entering into any infertility treatments. When I order the anovulation Profile (a series of blood tests), I simply want to determine if responsibility for your ovulatory disturbance lies with another condition such as thyroid disorders, diabetes, age related ovarian failure, stress infection, ovarian cysts, or pituitary or ovarian tumors. Once these conditions have been ruled out and a normal semen analysis and tubal patency has been confirmed, a treatment plan can be considered.
Traditionally, the first step has been clomiphene therapy regardless of whether or not PCOS was diagnosed. Studies report ovulation rates of up to 80% and pregnancy rates in approximately half those who ovulate have demonstrated in the literature using this method. However, in women with PCOS, miscarriage rates once conception occurs have been higher than normal, running as high as 60% loss in those women with a history of a prior loss. Multiple birth rates may be higher and ovarian hyperstimulation more frequent when using clomiphene therapy.
However, it appears that ovulation therapy in Hyperinsulinemic PCOS patients with metformin when combined with a low glycemic diet and a moderate exercise program may provide much better results and provide significant health benefits. Ovulation rates by three months of metformin therapy appear similar to clomiphene, yet the rates of multiple births, miscarriage and gestational diabetes may all be reduced. Added health benefits may include normalization of elevated blood pressure, weight loss, normalization of blood lipids, and better sugar control in diabetics.
First do no harm. That means , before starting the Metformin therapy, please confirm if your PCOS patient has Insulin Resistance. I ask for a 12 hour fasting Serum Insulin Test. If this value is more than 10, I consider the patient Hyperinsulinemic. My approach to metformin therapy is to start the medication gradually. During the first week a single tablet of the Metformin 850 mg is taken with a full glass of water toward the end of a meal. After a fortnight an additional tablet is added with another meal. This gradual introduction of the 1700mg full dose adds to patient compliance with minimal upset stomach or diarrhea, the usual transient side effects when starting this medication.
But, what happens if this approach does not restore fertility? At that point I will consider use of ovulation induction with or without intrauterine insemination. Clomiphene or the oral anti-estrogen medicine letrozole which is administered in a fashion similar to clomiphene are the first medications considered. Despite the failure to respond in prior attempts at clomiphene therapy when combined with metformin, the effectiveness of these oral medications is greatly enhanced. I must stress the importance of ultrasound monitoring at the start of each cycle to avoid significant ovarian hyperstimulation (OHSS). Many doctors don't realize that OHSS can occur even on clomiphene and don't bother to check the ovaries at the start of each treatment cycle. These women have a progressive increase in pain with each month of therapy and show up at the clinic with grapefruit-sized ovaries which require months off therapy to allow them to return to normal size before considering additional treatment. One last caveat is that if you have not conceived after three months of a particular therapy, it is time to meet with your physician to review your case and determine whether other therapies may be more appropriate.
One alternative that appears effective is laparoscopic ovarian drilling. For women who have a specific indication for diagnostic laparoscopy, this procedure should be considered. We prefer to use a monopolar needle placed into each ovary six to eight times. An electrical current is placed through the needle and ultimately destroys some of the male hormone (androgen) producing tissue in the central portion of the ovary. It is thought that excess androgen production interferes with normal follicle development. Those who demonstrate a normalization of male hormone levels after this procedure have the greatest benefit, while the procedure appears less effective in those who smoke. Despite successfully restoring ovulation in up to 80% of women, the expense and surgical risks make injectable therapy and IVF appropriate considerations.
In order to understand present day management with injectable medications, you must first understand a bit of the history surrounding these drugs. The first group of medications in this class were urinary derived hMG (Menogon, GMH), a mixture of two hormones, FSH and LH. FSH stimulates development of the follicle cells and the conversion of male hormones to estrogen. LH stimulates the production of male hormones and assists in the maturation of the egg. As the number of women in treatment increased, the demand for these drugs increased so drug companies were forced to consider alternative means to generate a sufficient supply of drug to meet the demand. This required large investments to produce pure recombinant (genetically engineered) forms of FSH (Gonal-F). Studies revealed that most women responded well to treatment protocols that included only FSH. They found that the body produced, on its own, sufficient LH to generate healthy eggs. It was surmised that since women with PCOS had high LH levels, they would do best using an FSH only product and avoiding LH entirely. We now know that may not be the case.We now do most of the treatment cycles using Menogon or GMH.
Let's look at this a bit closer. But first, a bit more basic review of the ovulatory process. Hormones work by attaching to the receptor on the outside of the cell and triggering some action inside the cell. In the early follicle phase (prior to ovulation), small follicles only have FSH receptors and therefore respond to FSH only. There are no follicular cell receptors for LH at this early stage. As the follicles grow FSH levels decrease and the follicles develop receptors for LH (approximately 12-14mm in size) and thus are able to respond to either FSH or LH by increasing the cellular levels of the chemical cyclic AMP. Smaller follicles lack LH receptors and as FSH levels drop, these smaller follicles die off. This fact has lead to a novel approach to ovulation induction that appears promising.
Initial work by Italian physician, Dr. Marco Filicori, has revealed that adequate continued growth and maturation of larger follicles can occur in the absence of FSH. He has shown that a switch to low dose hCG (equivalent to LH) promotes satisfactory follicular growth while smaller follicles die off. Well- designed studies will confirm whether this approach reduces the risk of ovarian hyperstimulation and multiple births. Additional studies will be required to determine whether this approach is appropriate for IVF patients where in many cases we find that "more is better" when it comes to the number of follicles that develop to maturity. We have found this result promising in a few patients whose prior cycles generated hyperstimulatory responses. I will consider this protocol in any patient who, during the course of stimulation, appears to develop an excessive number of follicles of varying sizes. We give micro-doses of hCG ranging from 50 IU to 200 IU. In addition to low dose hCG during the late follicular phase, follicular reduction (removal of eggs) or conversion to IVF with GnRH antagonist administration are alternatives to consider if excessive follicular development is noted.
These new therapeutic options offer exciting alternatives. Hopefully, well- designed studies will allow prediction of the best approach for each patient. Until that data is available, it is important that you consult your fertility physician to understand all possible alternatives and options prior to making treatment decisions.

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