Clomid and IUI

Fertility Treatments 101. Clomid and IUI (Intra-Uterine Insemination), a primer.

Previously I’ve had the great pleasure of the invitation to write about my experience with IVF as well as the nuts and bolts of a typical IVF cycle on this website.

But as I may have mentioned previously, all fertility treatments come with an increased chance of conceiving multiple babies. This is by virtue of the fact that treatments either tend to result in more eggs being ovulated than normal or placing more sperm in the vicinity of the eggs (eg IUI), or both, in order to overcome barriers to conception and increase the odds of a pregnancy.

So, in this article I shall take a step back and discuss less invasive fertility treatments.

This time I shall focus on oral fertility drugs for the woman (Clomid/Clomiphene and Letrazole/Femara being the most common examples in use) and IUI.

Clomid is commonly prescribed for women who have disorders of ovulation (infrequent or absent), for example poly-cystic ovarian syndrome (PCOS). Clomid, by nature of the way it works, is not effective in other causes of amenorrhea (absent periods) such as hypothalamic causes (extreme weight loss, dieting or exercise are common precipitants of this sort of problem) as it requires the hypothalamus and pituitary to be working normally.

How Clomid works.

Clomid comes from a class of drugs that have the formal name of estrogen receptor antagonists. This (to be slightly facile) does not mean that they are unusually argumentative in the presence of estrogen receptors in the body, but that they have the ability to bind to estrogen receptors and then block them- so that nothing happens.

To put it another way estrogen receptors all over your body (for example in your brain, uterus, and many other locations) in the normal state of affairs will have estrogen bind to them and in turn this causes a cascade of events to follow (for example again, in the case of your uterus, the lining grows and thickens in preparation for ovulation of an egg midcycle).

To back up even further, so the previous two paragraphs make more sense, the following is a brief explanation of what occurs in the course of a normal menstrual cycle:

Broadly put, there are three levels of control of the menstrual cycle:

• The hypothalamus (in the brain),
• The pituitary gland (also in the brain) ,
• The ovaries

These three areas talk to each other using several hormones:

• GnRh
• o made by the hypothalamus to communicate with the pituitary.
• FSH (follicle stimulating hormone) and LH (lutenising hormone),
• o both made by the pituitary gland to talk to the ovaries.
• Estrogen and Progesterone
• o Made by the ovary to prepare the lining of the womb for a potential fertilised egg.

The system works like a hierarchical system, with feedback loops so that each level knows what the others are up to. A diagram of how it all works would look roughly like this:
Explaining things further for a typical menstrual cycle (which has three main phases):

• Menstrual
• Follicular (ovulation occurs at the end of this phase)
• Luteal.

So, just to quickly recap before continuing further, there are three levels of control, three groups of hormones and three phases of the menstrual cycle.

Here’s what usually happens: Cycle day one, by convention, is considered the first day of full flow. At this point, estrogen and progesterone levels are low and the endometrium (lining of the womb) is shed because it relies on the presence of these two hormones.

In the follicular phase (first half of the menstrual cycle), the brain senses the low levels of estrogen, and in response the pituitary makes FSH. As can be seen from the diagram, FSH then stimulates the ovary to make estrogen by beginning to grow egg follicles.

As these egg follicles grow bigger, the estrogen rises (which the brain senses via it’s estrogen receptors), and in response to this the FSH begins to decline, thus the follicles compete for decreasing FSH until there is usually only one left. This is the follicle that is ovulated at midcycle.

Once the dominant follicle produces enough estrogen, a surge of LH (the other main hormone the pituitary talks to the ovary with) is triggered, which acts to mature and release the egg.

The second half of the menstrual cycle then begins, as LH levels rise. The LH acts to stimulate the remnant of the egg follicle that was ovulated (now called a corpus luteum) to make the progesterone which helps prepare the uterine lining for possible implantation of a fertilised egg.

If no fertilised egg implants, and signals the corpus luteum to continue producing progesterone by virtue of the hCG it makes, the corpus luteum breaks down and the cycle begins again with menstruation.

Here’s where Clomid and Femara come in. As I’ve already mentioned, Clomid blocks estrogen receptors. From the explanation provided above, it can be seen that if the receptors for estrogen are blocked in the brain, it can’t see that there are any egg follicles making estrogen. Therefore, in response to perceived low estrogen (because the receptors are blocked), more FSH is released.

More FSH means more signals to the ovary to grow egg follicles, and thus Clomid can help women who ovulate rarely or poorly to mature and release an egg.

Femara works in a slightly different way, but the net effect is the same- more FSH to stimulate the ovaries to grow a mature egg.

How is Clomid taken?

Clomid is usually taken for a total of five days in the early part of the menstrual cycle. The exact starting day is not important, and is usually acceptable anywhere from day 2 to day 5. There is some theory that taking Clomid earlier may develop more follicles, but the pregnancy rates are the same with either protocol.

A common starting dose is 50mg (one tablet), but women with PCOS may take less (25mg), and some women need more.

What to expect when taking Clomid.

Many women taking Clomid will notice few side effects. Those that do occur are usually related to the estrogen blocking effect of the medication- hot flashes, less vaginal mucus and sometimes spotting on the days the pills are taken. One of the reasons that increasingly high doses of Clomid are not usually prescribed is that as the doses get higher, the antiestrogenic negative side effects tend to increase which decrease the odds of pregnancy. These also include thinning of the lining of the womb and thickening of the cervical mucus, making it harder for sperm to get through.

Your doctor may monitor you via vaginal ultrasound scans to ensure you are making follicles in response to the Clomid and that your uterine lining is developing appropriately. You may also have a blood test at seven days post ovulation to confirm your progesterone is adequate.

Odds of success with Clomid.

In the absence of any other fertility issue, the odds of success of Clomid are about the same as natural conception- about 15-20% per cycle.

Because the control of how many follicles are maturing is not as fine as it is in the normal menstrual cycle, the chance of multiple pregnancy is higher, variously quoted as in the range of 6-10%. The great majority of these will be twins.


Generally up to six ovulatory cycles +/- IUI will be trialled before moving on to injectable FSH treatments.

IUI

In the normal course of events, many of the sperm that are deposited in the upper vagina in sexual intercourse are lost getting through the cervix, and further up into the uterus. Despite the fact that there may be many millions of sperm in a single ejaculate, relatively few of these will make it as far as the fallopian tube in order to fertilise an egg. It takes only one sperm to make a baby, but millions to get it there, simply put.

IUI is a treatment that bypasses the cervix and vagina and allows many more sperm than would usually make it into the uterus to get there, thus raising the odds of conception.

IUI is especially useful in situations where the cervical mucus is too thick to allow the sperm to swim though easily (as can happen with Clomid sometimes), or where there is milder forms of male factor infertility (borderline low counts, motility etc. See here for more of a discussion of infertility diagnoses).

It is a relatively simple procedure, much like a pap smear, where a fine catheter is threaded through the cervix. The prepared sperm (unprepared semen contains prostaglandins which can cause cramping of the uterus) is then injected into the uterus and from there makes it’s way towards the fallopian tubes as it would after sexual intercourse.

About the Author

About me, an introduction.

It’s funny how we describe ourselves in terms of roles in relation to others. I am no different.

I am someone who has experienced infertility and the various treatments firsthand. I am a terrible patient.

I am also a doctor (along with a few other tertiary qualifications I seem to have picked up along on dozen year plus meander through the university system and beyond), although that is often hard to believe at times, especially if you catch me at home smelling bottoms slightly too enthusiastically and exclaiming the following:

‘Sniff, Sniff. Okay. It smells brown. Who did poopy? Did YOU do poopy? (Nappy change) Oh-oh! Now it’s on my arm.’ And so on.

As opposed to immersed in the world of :

‘I have a 70 year old man who has presented with new-onset at xx o’clock crushing chest pain non-relieved by anginine on a background of stable angina and a previous AMI in year YYY for which he was thrombolysed with streptokinase. He has an ECG consistent with an evolving anterior infarct.’

Or some such waffle. I might even get to say ‘stat’ occasionally. If you’re really lucky, there’ll be a machine going impressively ‘beep’ somewhere in the background, too. Except these days, I’d probably substitute ‘whatsit’ for at least one word at some point throughout my shift because fatigue adversely affects my verbal fluency. If I’m ever your doctor and I look a little vague, please do forgive me. I know what I’m doing, it’s just that I have twins. All of the humour aside, I like to write, and I like to demystify. Especially about the machine that goes ‘beep’, although admittedly that doesn’t have much of a role in IVF. I’ll stop making bad Monty Python references now.

Simply put, my background gives me an interesting double-sided perspective on both the subjective experience of infertility as well as the objective science and I like to share it. Infertility is a quiet, rarely discussed problem that is not that uncommon.

In terms of my other major life role hinted at already, alternatively entitled my reproductive resume, I am the mother of six month old di/di IVF twin girls conceived after several years on the infertility treadmill. I am also someone who once had to make an incredibly difficult decision with regards to a much wanted pregnancy afflicted with a lethal anomaly, incompatible with extrauterine life. I have more experience in the worlds of both infertility and loss than I ever thought I would when I set out to have a baby in my late twenties.

In summary, think of me as a coffee clutching, slightly frazzle-haired thirty something wearing several hats at once. I am a spouse, a parent, a clinician and I like to dabble in writing in naptimes. Hopefully some of it proves helpful.

For more information on IVF procedure and infertility, you can visit Mission Impossible Infertile Also recommended is Stirrup Queens for information and support. Next up? How IVF works and the chances of having an IVF twin pregnancy.