"Injectables"

The term "injectables" refers to a group of fertility medications called gonadotropins.  They are given by injection, of course.  These medications either have FSH or FSH and LH in them.  FSH and LH are the two hormones the pituitary makes to get the ovaries to mature eggs and get them ready for ovulation.  In a natural menstrual cycle, several follicles (the sacs the eggs matures in) will start to grow.  It is a race, with each follicle trying to grow the fastest.  As the follicle in the lead grows, it produces lots of estrogen.  The estrogen from the lead follicle causes the amount of FSH being produced to decline.  The declining FSH levels keep the slower ones from being able to grow very well.  In the meantime, the lead follicle has made even more FSH receptors, and so it still get enough FSH to keep growing even in the declining FSH environment.  Once ovulation is triggered by the presence of a mature egg in the lead follicle, all of the others in the race either ovulate (if they are mature enough) or die.  Without fertility medication, one egg will usually make it to ovulation and the others die off.  If you flood the system with FSH from injections and keep the FSH levels high, you can level the playing field and get multiple eggs to mature at the same time.

There are several different brands of injectables.  Follistim, Gonal-F, and Bravelle all contain FSH without the LH.  Follistim and Gonal-F come premixed in a pen.  There is a barrel to the pen which contains the FSH, a dial at the top for entering to dose to be given, and then a small needle at the bottom.  The injection is usually given in the belly.  The medication needs to be placed just below the skin, not into a blood vessel or a muscle, so it is easy to do.  The amount of fluid that comes out is very small, and so it is not very painful at all.  If the thought of feeling the needle go through the skin is bothering you, anesthetic creams such as Emla can be used to numb the area before the injection is given.  The creams should be applied about an hour ahead of time for the best effect.  Bravelle comes as a powder in small glass vials.  You will also get another set of glass vials with saline in it (called the "diluent") to mix with the FSH powder and dissolve the FSH for injection.  They have a clever cap, called a "Q-cap".  The Q-cap goes onto the syringe with which you are going to give the injection.  The Q-cap with the syringe snaps onto the vial with the diluent, and you suck that up into the syringe.  You then snap the cap onto the vial with the powder, squirt the diluent into the powder, give a swirl or two to mix it, and suck it back up into the syringe.  The Q-cap is the removed and a needle is attached to the syringe for injection.  Bravelle can be given like the Follistim and Gonal-F (under the skin of the belly) or into a muscle (usually the buttocks).  Bravelle is what is called "highly purified FSH".  That means that the FSH is obtained from the urine of women in menopause.  It is then purified to remove other substances (please see previous blog on injectables for a more detailed explanation).  Both Follistim and Gonal-F are not obtained from urine.  They are made from what is called "recombinant DNA technology".  This means that the gene that codes for human FSH is placed into a group of cells in the lab, which are then stimulated to make the FSH from the gene.

Menopur and Repronex are injectables that are have both FSH and LH activity.  They are like Bravelle in that they are highly purified from urinary sources and are mixed with the Q-cap technology.  There are times when having LH stimulation along with the FSH is helpful.  Normally, women make enough LH that we don't worry about giving them extra.  Some women, however, have a condition where their bodies have decided that they are too thin or too stressed to make it safe to risk getting pregnant, so they don't ovulate (see previous blog on ovulation for more details).  These women don't make FSH or LH and so need both.  The other time that LH activity is useful is when large doses of FSH are being used, such as in IVF (in vitro fertilization or the "test-tube baby procedure").  When larges doses of FSH are given, it can confuse the pituitary, which usually makes both FSH and LH. The pituitary thinks its job is done, since there is lots of FSH around. It then doesn't make the LH.  Another way to get LH activity is to use hCG.  hCG is the hormone that is made in pregnancy, but it works on LH receptors.  The body can't tell the difference between the two.  As a matter of fact, I didn't quite tell you the truth in the first paragraph.  The LH activity in Menopur and Repronex is mainly from hCG that is added not LH.  So if Follistim or Gonal-F are used, small amounts of hCG can also be used to give the LH effect needed.

Injectables are usually used in combination with intra-uterine inseminations (IUI) or with IVF.  In both cases, the goal is to get multiple eggs ovulating.  When used with IUI, the goal is usually to get  approximately 3 eggs ovulating.  In IVF, we will often try to get 10-12 mature eggs.  In order to ensure that we are not getting too few or too many eggs, very careful monitoring is necessary.  An ultrasound to measure the size of the follicles and a blood test to look at the patient's estrogen level are done before the medication is started (usually about day 3 of the cycle).  The patient is then asked to take about 3 days of the medication (once a day, usually) and then brought back in for another ultrasound and estrogen level.  The doctor then compares the two ultrasounds and estrogen levels to see how fast the follicles are growing and eggs are maturing.  The dose is changed, if necessary.  The process of taking the shots and coming in for monitoring is then repeated every 1-4 days until the eggs are ready.  Once the eggs are ready, a large dose of hCG is usually given to get the eggs ready for fertilization and an IUI or IVF is performed.

Side effects of the injections are mainly from making the ovaries larger.  This can give you a heavy, achy sensation in your pelvis.  This can increase at the time of ovulation and feel like menstrual cramps for a while.  With larger doses, and therefore larger ovaries, you can feel full or bloated too.  Because each follicle makes estrogen, and you will have multiple follicles, your estrogen levels will be higher too.  This can make you feel a little nauseous, and will give you that stretchy mucus from the cervix that you usually don't see until ovulation.  So don't worry, you haven't ovulated early, the ovulation-type mucus is just early.  You can also notice more breast tenderness at the end of your cycle.  Estrogen does give some women a sense of well being and more energy than usual too.  They even get that nesting instinct that pregnant women get.  So if you find yourself organizing everything in site, it's the estrogen!  The injectables derived from urine can also cause fevers and flu-like symptoms on rare occasions (see the  blogs on injectables? and IVF, not so fast! for a description of my own experience with this side effect).

There are some risks to injectables as well.  The obvious one is multiple pregnancies.  As I have said before:  more eggs means more chance of pregnancy, but also more chance of ending up with triplets, quadruplets, etc.  That is why your doctor will monitor you closely.  He or she may even cancel a cycle, if there are too many eggs developing.  This is frustrating and disappointing, but nowhere near as bad as losing quadruplets in your fourth month of pregnancy before they are even viable.  So remember, your doctor has your best interests at heart.  If he or she is telling you that the cycle needs to be canceled, listen.  Multiples carry a high chance of miscarriage, prematurity, still birth, and birth defects.  Even careful monitoring cannot completely eliminate the risk of a multiple pregnancy, though, so keep that in mind.  If you are going to use injectables with IUI, you may want to have a conversation with your doctor and partner about what will happen if you do end up with triplets or more.  There are options, and it is easier to make decisions about what you would and wouldn't do before you are in the throws of the hormonal storm that is pregnancy.  IVF can reduce the risk, as we can control how many embryos are placed back into the uterus.  More and more, physicians are recommending that just one or two embryos be put back at a time with IVF to try to reduce the risks.  Therefore, if you doctor is giving you the choice of IVF or IUI with injectables, seriously consider doing the IVF.  The chances of getting pregnant are better and the risk of multiples is lower.

The other risk to injectables is something called Ovarian Hyper-Stimulation Syndrome (OHSS).  This occurs when the ovaries overreact to the medication.  Sometimes you will see signs that this is going to occur before ovulation.  In that case, canceling the cycle and keeping ovulation from happening will prevent the OHSS.  Using a medication called Lupron to trigger ovulation instead of hCG can also be helpful.  More often, though, it happens after ovulation or after the eggs are taken out for IVF.  With ovulation or the egg retrieval, most of the fluid in the follicles either bursts out or is taken out.  The ovaries become smaller, and the bloating and fullness gets better.  With OHSS, however, the follicles are still going and they fill back up with fluid.  So the first sign we usually see is that he patient starts getting bloated or feeling full all over again.  At that point, we bring the patient in to the office to see exactly what is going on with the ovaries.  To treat OHSS, we ask the patient to take it easy and don't do a lot of running around.  This may mean that you get put under "house arrest".  This is all that is usually needed to make the OHSS better, but it may take a few days or even a week or two to happen.  In rarer, more severe cases, fluid also starts accumulating in the belly as well as in the ovaries.  These women will be more bloated and uncomfortable.  In this case, we can put a needle through the wall of the vagina (we use anesthesia, don't worry!) and drain the fluid out.  This usually makes the patient feel significantly better immediately.  In extremely rare cases, fluid can accumulate around the lungs or heart.  This often requires that the patient be hospitalized and monitored closely.  That is why we monitor patients taking injections so closely, to keep that from happening.  With the newer, finer control of medication doses in the pens, it is also less likely to happen.  I haven't seen a case of severe OHSS with fluid around the heart, for instance, in about a decade.  Pregnancy can also cause OHSS after injectable medication.  Pregnancy hormone stimulates the ovaries to make progesterone, which is necessary for pregnancy.  In stimulating the ovaries to make progesterone, the ovaries can also be stimulated to grow bigger.  It is not dangerous to the pregnancy at all, but it will take longer for the OHSS to resolve than without a pregnancy.  Multiple pregnancies can cause even worse OHSS, which is another reason to try to avoid them.

Hopefully, I haven't scared you too much.  Injectables should be treated with a healthy amount of respect.  In the hands of a well trained doctor with access to monitoring, however, the risks can be minimized and the benefits can be wonderful!