Infertility Causes > Woman > Ovulation

Side Effects of Clomiphene
Clomiphene is associated with a fair number of side effects. A small percentage of women will experience mild headaches, bloating, hot flashes or visual symptoms (you should notify your physician if you experience visual effects). A rather large percentage of couples report that the use of clomiphene results in some emotional instability. If you are taking clomiphene and find that your emotions are a little hard to control, especially in the second half of the cycle, blame it on the clomiphene.

There are no known risks to the fetus or adverse effects on the infant should conception occur. Ovarian cysts may occur in some individuals on clomiphene, but if no additional clomiphene is given, the cysts will almost always resolve on their own. For this reason a pelvic exam or an ultrasound should be performed between cycles of clomiphene to be sure the ovaries have returned to normal before more clomiphene is taken. There is some increase in the risk of multiple pregnancies with clomiphene. Women who conceive have about a seven percent chance of twins. The risk of triplets, quadruplets, etc. is not really increased.

Other Considerations Concerning Clomiphene
Either a dose works, or it doesn't.  If taking fifty milligrams a day does not result in normalization of ovulation (and therefore your cycle) one month, there is no point in trying that dose again. The dose needs to be increased the next month. More is worse, not better. Once the dose that normalizes the cycle and results in good ovulation and progesterone production is determined, there is no point in increasing the dose further.  In fact, increasing the dose further may actually make it harder or even impossible to get pregnant.  Remember: Clomiphene functions by preventing the pituitary from seeing the estradiol that is present. It does the same thing to the cells that produce the cervical mucus and to the cells that line the uterusCif they don't see the estradiol, the cells of the cervix won=t produce the mucus, or the cells lining the uterus won't develop to an extent adequate to allow implantation.  Everyone has a threshold dose of clomiphene (the dose that normalizes ovulation). Going beyond that dose does more harm than good.

Clomiphene is an antiestrogen. This means that it does indeed prevent some cells from seeing the estradiol and because of this blocks the action of estradiol on those cells. The possibility of this type of effect needs to be checked once the threshold dose is achieved. This should include a post-coital test to be sure that there is adequate cervical mucus production, and a measurement of the thickness of the endometrium by ultrasound to be sure that it is developing to an adequate thickness. Normal endometrium develops to about ten millimeters in thickness; an endometrial thickness of seven millimeters or less is associated with very poor pregnancy rates. This is often a problem at some of the higher doses of clomipheneC although it results in ovulation, there is enough of an antiestrogen effect on the cervical mucus or endometrium to prevent pregnancy from occurring even though ovulation is normalized.

The vast majority of the pregnancies that occur as the result of the use of clomiphene occur within the first four ovulatory cycles. Once the threshold dose is achieved, there is really little point in pursuing the use of clomiphene beyond four, or certainly six, cycles at most. (The chances of conceiving in a cycle of clomiphene beyond the fourth may be as low as three to four percent, and decrease even further soon thereafter.)  There is another reason for limiting the number of cycles of clomiphene. There is at least one study suggesting that the use of clomiphene for more than a year is associated with an increase in the risk of ovarian cancer.

Finally, and perhaps most importantly, there is no role for clomi-phene in a woman with regular ovulatory cycles. There is absolutely no good evidence that clomiphene improves pregnancy rates in women with normal cycles. It is not a  fertility enhancer and, in fact, because of its anti-estrogen properties, it can actually make it harder to get pregnant rather than easier.

Progesterone
Progesterone is often used by itself or in conjunction with other ovulation-induction medications. Administering progesterone during the luteal phase directly increases the progesterone level. It is often used when there is concern about a possible abnormal luteal phase or luteal phase defect. Only progesterone, the same hormone produced by the body, should be used. The use of natural progesterone has not been associated with any risk of abnormality of the child. There are many progestins, or progesterone-like medications available, but many of these have been associated with birth defects. As far as anyone knows, pure progesterone is perfectly safe to use.

hCG
In nature's way, the pituitary produces large amounts of LH when the follicle is mature and the egg is ready to be released. This LH surge induces the final changes that result in egg release. hCG is a hormone produced by the placenta during pregnancy. Its structure is remarkably similar to LH, and the ovary really can't tell the difference between the two hormones. We can, therefore, use hCG to mimic the actions of LH. (Preparations of pure LH are not yet available.) When other ovulation medications are used, such as higher doses of clomiphene or the gonadotropins, the pituitary is no longer capable of adequately signaling the ovary with an LH surge. This signal must therefore be provided, and we do so by administering hCG. In most cases, ovulation will occur thirty-six to forty hours after the administration of hCG.
Smaller doses of hCG are often given during the luteal phase. These smaller doses of hCG provide stimulation to the corpus luteum to make progesterone. If luteal phase hCG is being used, one must be somewhat careful about the timing of a pregnancy testCpregnancy tests detect the presence of hCG, and doing the test too early will simply detect the hCG that was administered.

THE GONADOTROPINS: PERGONAL, METRODIN, HUMEGON, FERTINEX, FOLLISTIM AND GONAL-F

Pergonal, Metrodin, Humegon, Fertinex, Follistim and Gonal-F are collectively known as gonadotropins. Pergonal and Humegon are formulations of  LH and FSH, while Metrodin, Fertinex, Follistim and Gonal-F are FSH alone. For purposes of discussion, these hormonal preparations can be grouped together as the gonadotropins. There is very little difference in their action, and they can essentially be used interchangeably.

The gonadotropins function by directly stimulating the ovaries. The pituitary normally produces FSH and LH to stimulate the ovaries; by using the gonadotropins, this level of stimulation is directly increased.
Gonadotropins can be used alone or in combination with a GnRH agonist (see below). Administration is begun between day three and five of the cycle and usually continued for a total of five to nine days depending upon the response. One of the primary goals of gonadotropin therapy is to induce multiple-egg development. The ovulation of multiple eggs and the resulting production of higher hormone levels explain the conception rates associated with the use of gonadotropins. Whereas the use of clomiphene typically results in the production of only one or two eggs, gonadotropins can induce any number of eggs to develop, from a couple all the way to thirty or more. Their use must, therefore, be carefully monitored and supervised by a physician familiar and comfortable with their use.

Monitoring Gonadotropins
The response to the gonadotropins is usually monitored with a combination of estradiol levels and pelvic ultrasounds. The ultrasounds allow the physician to see the number of follicles and eggs that are developing. When a follicle reaches a certain size, around eighteen millimeters in diameter, the likelihood is greatest that the egg contained therein is mature. Thus, we can get not only a good indication as to the maturity of the follicles and eggs, but ultrasounds also provide a very clear picture of how many are mature and capable of ovulation. The estradiol levels also give some indication as to the health and well-being of the developing follicles. When the follicles are mature size, hCG is given and ovulation will occur thirty-six to forty hours later. 
In contradistinction to clomiphene which works by tricking the pituitary to increase its stimulation of the ovaries, the gonadotropins act directly on the ovaries. Rather than any type of antiestrogen effect, therefore, estradiol levels and the effects of estradiol are actually dramatically increased with the gonadotropins. For example, the gonadotropins enhance rather than impair cervical mucus production. 

Risk Factors of Gonadotropins
There are relatively few side effects associated with the gonadotropins. Aside from the emotional roller coaster that all couples experience while attempting to conceive, there are no significant emotional side effects associated with the menotropins. The two most frequent problems are enlarged ovaries and multiple births. It is normal for the ovaries to be enlarged after the use of the gonadotropins; we have, after all induced three or four (and sometimes more) eggs to develop and ovulate.  Most of the symptoms associated with this enlargement occur after ovulation, during the luteal phase when three or four corpora lutea (plural of corpus luteum) are actively producing progesterone. Simply decreasing one=s activity level is all that is usually necessary.  In more severe cases, hyperstimulation may occur.

Multiple Pregnancies. Anyone initiating treatment with the gonadotropins must realize that multiple pregnancy is a possibility. Twin pregnancies occur as frequently as twenty percent of the time in women who conceive on gonadotropins.  And everyone has heard the stories of women who have conceived far more than twins.  However, higher order multiple pregnancies (triplets or more) don't have to be a significant risk to women on gonadotropins. Remember, the response to the gonadotropins is monitored with ultrasound. The number of  follicles and eggs that are developing can be seen prior to giving hCG to trigger ovulation. If an unacceptable number of follicles develops, we simply don't give the hCG; ovulation doesn=t occur and the cycle is wasted, but a canceled cycle is better than a litter! There is no hard and fast number that constitutes an acceptable number of follicles. That depends on many factors including the number of previous attempts, age and other factors involved. This is why one should have an expert monitoring their cycle, so these types of information can be considered and carefully thought out decisions made.

Ovarian Cancer.
There has been some concern raised that the use of the gonadotropins is associated with an increased risk of developing ovarian cancer. This issue has been very carefully evaluated, and the data does not support such an association. It does seem that there may be a group of women with ovulatory dysfunction who are at increased risk of devel-oping ovarian cancer with or without treatment. However, for the average women using gonadotropins, there is no evidence that this use is associated with an increased risk of ovarian cancer.

Other Considerations
The two major drawbacks to the gonadotropins are expense and the fact that they must be administered by injection. These hormones are very expensive, and one cycle can cost as much as $1,000 or more. Pergonal, Humegon, and Metrodin are given intramuscularly in the hip. We usually teach the husband to administer these shots. Fertinex, Follistim, and Gonal-F are given subcutaneously and can most often be self-administered.
Follistim and Gonal-F are the most recently approved gonado-tropins. These two hormone preparations are produced by recombinant DNA technology, meaning that they are produced in the laboratory rather than isolated from human urine. They are purer preparations of FSH.
There is little if any reason to record a BBT chart while on the gonadotropins. All of the other monitoring provides more than enough information about the cycle. Progesterone levels are also checked during the luteal phase, and the length of the luteal phase is easily determined since the time of ovulation is known. All of this data provides more than enough information about the adequacy of the cycle.

The gonadotropins should only be used every other month at most.  It is simply too much for the ovaries to use them every month; the ovaries need at least a month in between to recover. There is a lot of debate as to what is the maximal number of cycles one should attempt with the menotropins. Much of this will depend on a number of considerations that were discussed in Chapter 6, but suffice it to say that the chances of successful conception make it hard to justify more than three attempts in most situations. If conception has not occurred within three attempts, an ART procedure should be considered.

GNRH AGONISTS
GnRH is a hormone produced by the hypothalamus. The hypo-thalamus is control central. It controls many of the basal functions of the body, including reproduction. It controls reproduction by controlling the production and release of LH and FSH from the pituitary. GnRH agonists, such as leuprolide acetate (Lupron) and nafarelin acetate (Synarel), very selectively inhibit the ability of the pituitary to produce and release LH and FSH. If LH and FSH aren=t produced, the ovaries are not stimulated. In other words, by using Lupron we can temporarily turn off the ovaries.

There is a good rationale for doing this, for turning off the ovaries before we begin to stimulate them with the gonadotropins. Remember that egg development for the upcoming cycle actually begins late in the previous cycle. The timing of the beginning of this development varies, but progesterone usually suppresses this development until late in the luteal phase. In some women, particularly those who produce relatively low levels of progesterone, the development of the eggs for the next cycle may begin too early. If the gonadotropins are begun on day five, the development may have already progressed far enough that the goal of gonadotropin therapy,  i.e., improved quantity and quality of follicles, is unattainable. When the GnRh agonists are used, complete suppression is achieved. Thus, when the gonadotropins are begun, we are starting with a clean slate. No follicle and egg development has occurred, and stimulating and controlling their development from the very beginning is possible.

The ovaries are most easily suppressed by beginning the GnRH agonist in the luteal phase, usually about day twenty-one. This does imply, silly as it may sound, that you should not attempt pregnancy in a month in which you anticipate starting a GnRH agonist on day twenty-one. There are a fairly large number of cases in which an agonist has been started and a pregnancy has occurred, and there do not appear to be any adverse effects.  However, why chance it? After starting the agonist on day twenty-one, the next period will probably be relatively normal and will probably occur on time. An ultrasound is performed soon thereafter, and if the ovaries have been suppressed, the gonadotropins are begun. Using a GnRH agonist in conjunction with the gonadotropins has several advantages:

Premature ovulation will not occur. Ovulation will occur about forty hours after the administration of hCG. 

The follicles and eggs that do develop in response to the gonado-tropins are more synchronous in their development. Their maturity levels are about the same.

It may be far easier to get more than one follicle to develop by adding a GnRH agonist than it is with the gonadotropins alone.

Luteal phase progesterone, both in terms of levels and duration of production, is improved.

There are several indications for adding a GnRH agonist to the gonadotropins. A history of premature ovulation, difficulty getting more than one follicle to develop, and poor progesterone levels or short luteal phases while on the gonadotropins alone suggest that a GnRH agonist would be worthwhile. The combination of a GnRH agonist and gonadotropins is often more effective in correcting a significant luteal phase insufficiency than are gonadotropins alone.
The GnRH agonists are administered either by subcutaneous  injection (Lupron) or by nasal spray (Synarel). When used for this purpose, they have few if any side effects. Addition of a GnRH agonist does usually result in the need for additional gonadotropins to achieve adequate ovarian stimulation.

PARLODEL AND DOSTINEX
Parlodel and Dostinex are medications that specifically and effectively decrease the production of prolactin from the pituitary. As noted above, prolactin levels should be checked in anyone with cycles that are anything but perfectly normal. If the prolactin level is above fifty, some radiological evaluation should be performed prior to initiating treatment to see if a pituitary microadenoma is present (these are benign tumors in the pituitary that produce prolactin). Treatment with Parlodel and Dostinex should be initiated and adjusted until the prolactin level is back in the normal range. Nausea, which is one of the more common side effects of Parlodel, can be avoided by simply placing the tablet in the vagina rather than swallowing it.

 
LUTEAL PHASE INSUFFICIENCY
There are some women who, although they may ovulate regularly, do not produce adequate progesterone or who produce progesterone for a shorter period of time than they should. This results in the lining of the uterus receiving inadequate stimulation or support to undergo the series of changes necessary to allow implantation to occur. Thus, although concep-tion may occur, pregnancy does not because of failure to implant.

There are several factors associated with luteal phase insufficiency, including a low percent body fat, elevated prolactin levels and even stress. Luteal phase insufficiency can be diagnosed by checking progesterone levels in the mid-luteal phase, by careful evaluation of BBTs and bleeding patterns or by endometrial biopsies. I do not believe in endometrial biopsies for this purpose. They are invasive, potentially painful, costly and unnecessary.  Progesterone levels and BBTs will provide adequate information about the luteal phase in most women. If these are adequate, there are very few women indeed for whom an endometrial biopsy will reveal a problem.

This approach of not doing endometrial biopsies may miss a small percentage of women in whom only the endometrial biopsy would reveal an abnormality. However, the approach to treatment for these women will be the same if we do a biopsy and reveal an abnormality as it would be for women with unexplained infertility. We would initiate the same treatment whether or not we have the results of an endometrial biopsy. So why do it?  This group of women with possible luteal phase insufficiency should just be treated like women with unexplained infertility. In other words, if the treatment is going to be the same anyhow, why not just proceed with that treatment rather than performing a lot of testing that is not going to change the treatment.

Luteal phase insufficiency can be treated with progesterone sup-positories, low-dose clomiphene given on days three through seven, hCG at the time of follicular maturity or a combination of any or all of these. If this is unsuccessful, combined GnRH agonist and gonadotropin therapy seems to be far more effective in correcting luteal phase insufficiency than are gonadotropins alone.  

HYPERSTIMULATION
Ovarian hyperstimulation syndrome (OHSS) is a syndrome that can occur in the luteal phase following the use of gonadotropins (and rarely after clomiphene). Following the development of multiple follicles, multiple corpora lutea develop. As a result of this, the ovaries enlarge, usually to an insignificant level but sometimes to as much as eight or ten centimeters or more. The extent of enlargement is proportional to the number of corpora lutea present and can be somewhat predicted by the level of estradiol prior to hCG administration at the time of ovulation. Most women on gonado-tropins will experience some symptoms of hyperstimulation with bloating and some ovarian tenderness being common. These symptoms are usually mildCyou may want to wear baggy sweat pants rather tight jeans and may not feel like going to aerobics class. But usually normal activity can be pursued. More severe hyperstimulation is uncommon and is more likely to occur when these medications are intentionally used to achieve the development of more than just a few follicles (such as in an ART procedure). In severe hyperstimulation, the ovaries are very enlarged, and fluid may accumulate in the abdominal cavity. Women may experience bloating, difficulty breathing, weight gain and decreased urine output. Although unusual, this can require hospitalization for management until the ovaries begin to return to normal size. If a woman does not conceive in a cycle using gonadotropins, the ovaries will return to normal quickly after the period begins. If pregnancy does occur, it may take several weeks for the ovaries to return to their normal size.

POLYCYSTIC OVARIES
A special subset of ovulatory abnormalities is known as polycystic ovary syndrome, or PCOS. There are many variants of PCOS, and the process can be mild to very severe, but virtually all women with PCOS have a history of irregular menstrual periods, usually since the time of puberty.  The menstrual cycles are irregular because women with this process ovulate very irregularly, and in some cases not at all. Other symptoms or signs that may be associated with this process include infertility, excessive hair growth and obesity. 
 
It is not known what causes some women to develop PCOS. There is evidence that some individuals may inherit the process from their mothers, but for most individuals the events that result in the development of this process are unknown. We do know, however, that virtually every woman with PCOS has elevated insulin levels in her blood, and it is felt that these insulin levels may be directly responsible for the abnormalities seen in PCOS. In fact, there is some evidence that exposure to high insulin levels at the time of puberty may result in the development of PCOS.

Once this process gets initiated, the regular cyclic events that result in normal menstrual cycles do not occur. Rather, PCOS is characterized by a very constant hormone picture day after day. The pituitary produces higher levels of LH than are found in normally cycling women. The ovary responds to this higher-than-normal level of LH by producing higher-than-normal levels of  male hormones, specifically testosterone. (This is exactly what the ovaries are supposed to do in response to high levels of LH. The higher-than-normal levels of testosterone are responsible for the increased hair growth which is often noted.) The testosterone is then converted by other tissues, specifically the fat cells, into estrogen. The hypothalamus then Asees@ the high levels of estrogen and responds perfectly normally by telling the pituitary to produce more LH and less FSH. The pituitary produces more LH, and the whole thing becomes a vicious cycle. In addition, the lower-than-normal levels of FSH decrease the stimulation to the ovary that is needed in order for an egg to mature to the point where it can be ovulated.  In other words, every part of the system is responding appropriately to the signals it is receiving; it=s just that somewhere along the line something got mixed up. A vicious cycle is established and will continue until something happens to break the cycle.
Diagnosing PCOS is pretty straightforward. If a woman has a life-long history of irregular periods, she probably has PCOS. It is not necessary to have blood drawn for LH and FSH levels to diagnose this process; the history is good enough. If excess hair growth is present, the physician may want to check a testosterone and DHEA-S level just to be sure there is no tumor producing those hormones. If a pelvic ultrasound is performed, it will reveal many small (rarely more than a few millimeters in diameter) cysts in the ovaries. These are small follicular cysts that have begun development but have not progressed beyond this size because of the relative lack of FSH.
 
For women who do not want to be pregnant, birth control pills are an excellent means of managing PCOS. The birth control pills suppress LH, thereby suppressing the ovaries and decreasing their production of hor-mones, including testosterone. Birth control pills also result in normalization of the periods.

Clomiphene was designed for use in women with PCOS. Clomi-phene prevents the pituitary from Aseeing@ the amount of estrogen that is present. If the pituitary doesn=t Asee@ any estrogen, it responds by decreasing the production of LH and increasing the production of FSH.  This is exactly what is neededCthis is one way to break the cycle. If the FSH levels are increased enough, the ovary will respond by maturing one or more eggs and ovulation will occur. As many as ninety percent of women with PCOS will ovulate in response to clomiphene, with about half that many becoming successfully pregnant.

There are, however, certainly individuals with PCOS in whom clomiphene is unsuccessful; in spite of maximal doses of clomiphene, ovulation does not occur. These individuals are then candidates for ovulation induction using gonadotropins, either alone or in combination with a GnRH agonist. This can be somewhat tricky. Remember, there are lots of little follicles sitting in the ovaries just waiting for some FSH to come along.  Women with PCOS are at increased risk for producing large numbers of eggs in response to the gonadotropins, and consequently their risk for ovarian hyperstimulation is also increased. This excessive ovarian response can be managed by performing an ART procedure, which gives the physician the opportunity to remove all of the eggs, and return only the number appropriate for an individual of that age. Thus the risk of multiple pregnancies can be safely controlled.
 
There are also surgical approaches for dealing with PCOS. The earliest treatment of PCOS was, in fact, a surgical procedure known as a wedge resection, in which a significant part of the ovary was removed. This procedure worked because it broke the cycle by decreasing the amount of testosterone produced from the ovaries. It is, however, rarely performed anymore because of the need for major surgery, the risk of formation of scar tissue after this procedure, and the availability of medical therapies. There are, however, laparoscopic procedures in which much the same thing is accomplishedCpart of the ovary is destroyed. The risk of forming scar tissue after a laparoscopic procedure for PCOS is significant. Furthermore, any type of procedure in which part of the ovary is destroyed results in temporary improvement only. Eventually the PCOS pattern will return. Surgical therapy is, therefore, usually reserved for individuals whose PCOS cannot be managed with the medical therapies listed above.

One of the most exciting developments in the area of PCOS is an increased awareness of the role of elevated insulin levels in this process. There are medications available (e.g., Rezulin, Glucophage) for the treatment of adult-onset diabetes mellitus that specifically reduce insulin levels in the blood. Preliminary studies have demonstrated that insulin levels in individuals with PCOS can also be reduced by using these medications. These studies have also demonstrated that, by reducing insulin levels, many of the abnormalities of PCOS can be reversed and in many cases the ovaries will begin to function normally. In virtually all women with PCOS treated with insulin-lowering agents, ovarian function is improved. Although further study and evaluation of these agents is needed (and these studies are currently underway in our center as well as others), they hold great promise, and they may well be the way PCOS is managed and treated in the near future.

© 2005 Jarrett Fertility Group