Gonadotropins in IVF: How Do They Work and What Are the Risks/Side Effects?
Gonadotropins are hormones produced by the pituitary gland which stimulate sex hormone production as well as gamete (sperm and egg) production in the man /woman. Through causing follicle/egg and sperm development and eliciting sex hormone production they are ultimately responsible for reproductive aptitude and performance as well as the expression of secondary sexual characteristics. There are two gonadotropins, Follicle Stimulating Hormone (FSH) and Luteinizing Hormone(LH). These gonadotropins are excreted in the urine. Two varieties are commercially available. The 1st is menotropins or urinary-derived Human Menopausal Gonadotropins (hMG). The 2nd is genetically-engineered Recombinant DNA-gonadotropins, (FSHr and LhR).
If administered to women at a sufficient dosage beginning early enough in the menstrual cycle, commercially available gonadotropins will prompt the development of multiple follicles each of which houses oner egg. The average number of eggs retrieved from a woman younger than 35 after gonadotropin stimulation (provided she has two ovaries) is usually between 6 and 20, though in normally ovulating women-under 30 years of age. Women with dysfunctional or absent ovulation [e.g; 1. women who do not menstruate at all (amenorrhea) 2. women who menstruate irregularly and 3. women who polycystic ovarian syndrome (PCOS)] often are very high responders to gonadotropins, often producing more than 25 follicles at a time. Such women are often at risk of developing a potentially life-endangering condition known as severe ovarian hyperstimulation syndrome (OHSS) see below. The wide variation in response to gonadotropins mandates that those administering such medications have the experience necessary to avoid such risk and the ability to treat OHSS effectively, should it occur.
1. Urinary-Derived Gonadotropins (Menotropins): these are derived from the urine of post-menopausal women whose pituitary glands, in response to a feedback message that their ovaries are no longer producing enough estrogen, greatly increase their output of both FSH and LH. The excess FSH and LH produced hormones produced asre then excreted in the urine from which after collection, distillation, filtration and purification the FSH and LH are extracted.
a. Human Menopausal Gonadotropins (hMG)– Menopur, Merional: hMG contains both FSH and LH. Menopur also contains a small amount of added hCG. Presently, each vial of hMG (75 units) costs about $70 in the United States. The average woman undergoing ovarian stimulation for IVF might require 25 or more vials of hMG per treatment cycle. LH (and hCG) directly stimulates the tissue surrounding the ovarian follicles (ovarian stroma or theca) which in response produces male hormones (predominantly testosterone). The testosterone is then carried to the surrounding follicles where FSH converts it to estrogen (estradiol). It follows that some LH is thus essential for normal follicle growth and development. The problem arises when there is too much LH, because in such cases testosterone will often be produced in excess in which case it can adversely affect follicle growth and with it, egg development. Excess ovarian testosterone can also access the uterine blood where it can blunt response of the endometrial lining to estrogen and in so doing compromise endometrial development. In this way, ovarian male hormone production induced by LH could either benefit or impede egg/embryo development as well and IVF outcome. Correspondingly, it can either enhance or hinder embryo implantation in the uterine lining. Women over 40 years and those who have diminished ovarian reserve often have elevated blood LH levels and their ovaries often produce an overabundance of testosterone in response to the LH. Accordingly, ideally such women should not receive too much LH-containing drugs such as Menopur or Merional, because this could compromise egg quality and endometrial development.
b. Urinary-Derived FSH-(Bravelle) this is essentially hMG that has been processed further to extract most of the LH. It is less expensive than FSHr (see below) but in my personal opinion, is not as effective. Moreover, uri nary-derived gonadotropin products tend to exhibit a more variabe dose-related response, probably because of a significant batch-to-batch variation in biopotency. Accordingly, I tend to avoid prescribing Bravelle to my IVF patients.
2. Recombinant DNA-Gonadotropins
a. Recombinant FSH (FSHr): hMG has in recent times largely been supplanted by purified FSHr (e.g. Folistim, Gonal-F and Puregon) which are derived by way of genetic engineering. FSHr appears to be more bioactive than urinary-derived FSH products such as Bravelle and hMG and response to FSHr, more consistent and predictable.
b. Recombinant LH (Luveris): Since some LH is essential to provoke the ovarian stroma to produce some testosterone for delivery to the follicles for conversion into estrogen, a small amount must be given with FSHr to achieve egg development. Rather than using menotropins (that contain LH/hCG), I prefer to use LHr and administer this along with FSHr to my patients.
3. Combined Clomiphene + Gonadotropins: in the late 80’s and early 90’s many IVF programs prescribed a combination of clomiphene and gonadotropins for controlled ovarian hyperstimulation. The stated reason for doing so was the belief that clomiphene would improve the ovary’s sensitivity to gonadotropins, thereby reducing the dosage of gonadotropins that would be required to achieve effective follicle development. Thus, since clomiphene is much less expensive than gonadotropins, the overall cost of fertility drugs could be significantly decreased. A second cited reason for administering these drugs in combination was to simplify their administration (clomiphene can be taken in pill form although gonadotropins must be injected. Today, because of reduced efficacy, the vast majority of IVF programs in the United States no longer use this combination).
In my opinion the administration of combined gonadotropins/clomiphene has several drawbacks. First, because clomiphene has the ability to induce ovulation, a combination of clomiphene and gonadotropins may cause spontaneous ovulation even without the subsequent administration of the hCG ntrigger. In such a case, ovulation might inadvertently take place prior to egg retrieval resulting in fewer eggs being harvested at egg retrieval, and the associated premature rise in LH that precedes ovulation can damage eggs. In addition, some physicians feel that the combination of the two drugs makes it difficult to pinpoint the amounts of each that would be required in cases where the overall dosage of fertility drugs needed to be adjusted in subsequent treatment cycles.
Because gonadotropins cannot be absorbed through the stomach into the bloodstream, they must be administered by injection rather than in pill form. While most hMg preparations are best injected intramuscularly, FSHr and LHr can readily be administered subcutaneously, thereby rendering the injections easier to administer and far less painful. The usual injection schedule is from day 2 or 3 through day 8-12 of the menstrual cycle.
One of the most significant attributes of gonadotropins is that until she receives the hCG shot, she will be very unlikely to ovulate. Thus, since OHSS cannot develop in the absence of hCG, by omitting the hCG trigger in certain patients this risk can be avoided even at a late stage.
Risks and Side Effects of Gonadotropin Therapy: some women taking gonadotropins report breast tenderness, backaches, headaches, insomnia, bloating, and increased vaginal discharge, which are directly due to increased mucus production by the cervix.
As referred to above, a potentially serious side effect of gonadotropin administration includes a condition known as severe ovarian hyperstimulation syndrome (OHSS). The condition usually starts with the development of many (>25 follicles), gross ovarian enlargement and “weeping” of the ovaries leading to excessive fluid exuding into the abdominal cavity. The excessive collection of fluid in the abdomen causes it to distend severely and this might even compromise breathing. In some cases, the kidneys or liver may fail and the woman may stop producing urine. In very advanced cases the blood loses its ability to clot and the woman can go into pulmonary and cardiac failure. OHSS is highly unlikely to occur in properly managed patients.
It is significant that gonadotropins are highly unlikely to produce any serious persistent side effects until the woman receives the injection of hCG to stimulate ovulation. Thus, the physician has ample time to assess her status and withhold the hCG if it appears that she might develop major side effects (such an assessment is made on the basis of blood estradiol values or ultrasound examinations immediately prior to administration of hCG). This built-in protective advantage shields almost all women being treated with gonadotropins (administered either alone or in combination with clomiphene) from the serious hazards of overstimulation.
Variations in Response to Gonadotropins: some women stimulate well after relatively small doses of gonadotropins. Others require two, three, or even four times that dosage to achieve the same effect. In the past, selecting the proper dosage was a trial-and-error process. There was simply no way to predict how a particular woman might respond. Each woman is unique, and each can be expected to react differently to gonadotropins. However, about 80% of women respond appropriately to an average injection.
We measure FSH and estradiol (E2) in the woman’s blood on the second or third day of a natural menstrual cycle preceding the IVF cycle. We also sometimes selectively measure antimullerian hormone (AMH), and Inhibin B to predict how she will likely respond to a variety of stimulation methods. We believe that these tests are also valuable in selecting the most appropriate dosage and regimen of fertility drugs to be administered.
Despite these refinements, however, stimulation for IVF is still somewhat of a hit-or-miss procedure. For example, when a woman has used up most of her lifetime egg budget and is left with less than a critical number of eggs, she begins to enter a phase of hormonal change known as the climacteric. The climacteric is associated with a loss of fertility, the onset of hot flashes, and mood changes. It ultimately culminates with the total cessation of menstruation between the ages of 40 to 55, a process called the menopause. The ovaries still produce hormones after menopause, but they are released in a constant rather than cyclical manner.
When a woman fails to be adequately stimulated with gonadotropin on the first try, the dosage and even the regime of treatment with fertility drugs must be adjusted for her next attempt.
Follicle growth and development, egg maturation, the number of eggs that can be retrieved, and the risk of side effects are directly related to the patient’s response as evaluated by blood-estrogen levels and/or ultrasound, not to the dosage of gonadotropins. Therefore, it is illogical and ill-founded to fear administering an escalating dosage of gonadotropins after a poor response to a standard dosage. What is important is to monitor the individual’s response to the drug.
It is only through individualized, proper management of ovarian stimulation that risk can be minimized and outcome, optimized.