One of the most common procedures in the treatment of human infertility.
The objective of ovulation induction is to stimulate the ovaries to develop one or more oocytes for fertilization by sperm cells. Normally ovulating women usually produce one oocyte every 28 days. With ovulation induction medication the number of oocytes can be increased and so the probability of pregnancy. The purpose of this article is to help you understand this process by increasing your knowledge of basic ovarian function, different medications used for ovulation induction, how the medications work, estimated pregnancy rates and potential side effects.
Organs and Hormones Involved in Reproductive Function.
The ovary and the brain are the main structures involved in reproductive functions. Communication among them is mainly by hormones released into the blood stream. The hypothalamus and the hypophysis or pituitary gland, located in the base of the brain, are involved in the synthesis and release of the Follicle Stimulating Hormone (FSH) and the Luteinizing Hormone (LH) respectively. These two hormones stimulate the ovary to develop the follicles containing the eggs or oocytes and are the ones utilized clinically by your physician to achieve the same goal. Daily production and release of FSH and LH are under inhibitory control by low levels of estrogen produced by the ovary. This means that when estrogen is present, there is minimal FSH and LH being released. The Gonadotropin Releasing Hormone (GnRH or commercially known as Factrel or Lupron), secreted by the hypothalamus upon the influence of increasing estrogen levels is in charge of inducing the LH surge prior to ovulation. On the other hand, the ovaries and more precisely the ovarian follicle, a blister like structure housing the egg or oocyte, produce estrogen and testosterone in response to FSH and LH respectively. Testosterone, produced upon the influence of LH, is converted into estrogen by the action of FSH in the follicle. As the follicle grows, it becomes more sensitive to FSH and LH and slowly the levels of estrogen start to rise prior to the LH peak preceding ovulation. Upon the influence of estrogen, the uterus starts to get ready for an eventual implantation by developing the endometrium or lining of the uterus. The LH surge shuts down estrogen production and marks the onset of progesterone production which will induce the final preparatory endometrial changes prior to embryo implantation. The same follicular cells which were producing estrogen now are in charge of progesterone synthesis and release under a different histological structure known as the corpus luteum. In the absence of implantation, the corpus luteum is destroyed, progesterone levels decrease and the endometrium is shed leading to menstrual bleeding.
Review of Ovarian Function.
Women are born with a limited reserve of oocytes, and this supply diminishes continuously during their life reaching critical numbers by age 40. A fetal ovary contains about 6-7 million oocytes by the 20th week of gestation. From mid-gestation onward there is a relentless and irreversible loss of oocytes by a process known as atresia. At birth, girls have lost about 80% of their initial reserve of oocytes, only one to two million are present in the ovaries at this time. The number of oocytes decreases even further to about 300, 000 by the onset of puberty. Of these oocytes, only 400-500 will ovulate in the course of a reproductive life span, less than 1% of the total number of initial oocytes. When the women are about 50 years old, the number of oocytes is exhausted and they enter the menopause.
In the fetal ovary, soon after they are formed, the oocytes are surrounded by a layer of supporting cells and enter a resting state where they remain until they resume growth. There are intra- and extra-ovarian factors that regulate oocyte growth. Little is known about those development intra-ovarian factors but once an oocyte leaves the resting stage to enter the growing phase it has two options: ovulation or death by atresia. The oocytes are constantly leaving the resting stage and continue their development. Even during pregnancy the oocytes are leaving the ovarian pool, and because they do not have the correct hormonal environment they stop growing and are lost. The oocyte development can be sustained after the onset of puberty with help of the reproductive hormones FSH and LH during normal menstrual periods. These two hormones would be the main extra-ovarian factors regulating oocyte development.
The oocyte in the resting state is surrounded by a number of cells that will support its development once it leaves the resting state. Those surrounding cells will develop in number and will form the follicle and become active under the influence of the reproductive hormones FSH and LH. The follicle is what you see in the ovaries at the time of ultrasound scanning. When the follicles grow they initially produce estrogen or Estradiol, which helps the uterine endometrium to develop. After the LH surge or hCG injection they switch functions to produce progesterone, which will prepare the endometrium for implantation. If no implantation occurs the lack of progesterone support will result in menstrual bleeding. And the cycle starts again.
During the menstrual period several oocytes/follicles leave the resting stage and upon the influence of FSH and LH start to form the follicle. As they continue their development they become more dependent on FSH and LH. If a leading follicle does not find the proper balance of these hormones, it stops its development and another follicle takes its place. The follicle that is destined to ovulate is the one that found the proper balance of hormones all along its development. Why is only one follicle ovulated in most of the occasions? There is an intense level of competition among follicles and the leading or dominant follicle releases a substance known as Inhibin, which inhibits the development of the other follicles. If the leading follicle stops developing then the level of inhibin secreted by that follicle decreases and another follicle takes over the lead and it starts to secrete its own inhibin to delay the development of the rest of follicles in the growing pool.
There are several important facts that we need to highlight from the previous discussion. Women are born with a limited number of oocytes. The oocytes leave the resting state everyday prior to puberty, during the menstrual cycles and even during pregnancy. Most of them will be lost by atresia for the lack of the proper stimulus to continue their development. It is not until puberty that women obtain the capability of ovulation as evidenced by the menstrual cycle. The follicle that is destined to ovulate is the one that found the proper balance of hormones (FSH and LH) during all its phase of development. This mechanism of oocyte losses is responsible for the women’s diminished reproductive potential once they are 35 years or older. It should be clear to you why only one follicle is ovulated during a normal menstrual period.
Main Causes of Female Infertility.
A broad classification of infertility suggests that it may be divided in factors blocking ovulation, fertilization, implantation or pregnancy. There are different conditions interfering in the specific stages described. A more clinical approach divides human infertility into:
Some of the factors that interfere with the woman’s ability to conceive are those related to ovulatory dysfunctions. The reproductive hormones play an important role in the treatment of ovulatory problems. Some women do not have ovulatory cycles (anovulation); others have irregular cycles (oligo-ovulation). These two conditions are not the main problem but a mere manifestation or symptom of another condition of greater significance. The conditions are quite diverse and may include problems with the central nervous system, endocrine system or problems within the developing follicles or ovary.
In other conditions, women fail to ovulate because there are not enough follicles in their ovaries. If this happens before the age of 40, the condition is called “Premature Ovarian Failure” or POF. Prior chemotherapy or radiation therapy while treating cancer, removal of the ovaries, genetic abnormalities, or patient specific factors are some of the conditions which result in depletion of the egg supply at a young age. In some cases, there is usually no obvious explanation and these women are believed to have exhausted their supply of oocytes at a young age for apparently no reason. When few or no oocytes are left in the ovaries the patients are no longer candidates for ovulation induction and they will benefit more from donor oocytes.
Failure to ovulate may be due in part to little or no stimulation coming from the pituitary gland. Insufficient LH and FSH to stimulate follicular development in the ovaries to maturity may lead to oligo-ovulation or anovulation. Treatment consists of either stimulating the pituitary gland to release LH and FSH by means of GnRH stimulation (see GnRH treatment) or to simply replace the missing LH and FSH by administering it directly (see gonadotropin stimulation)
Most women who fail to ovulate regularly have a normally functional pituitary gland and sufficient follicles containing oocytes in the ovaries. However, the problem apparently is related to the stimulatory effect of gonadotropins released by the pituitary or to the way the ovaries respond to the hormones. This is the case of the Poly-Cystic Ovarian Syndrome (PCOS) which is a condition characterized by the lack of ovulation including multiple small follicles within the ovary which are visible on ultrasound and abnormal levels of blood testosterone, LH and FSH. The cause for this disorder is poorly understood. Apparently there is a lack of FSH stimulation to ensure proper follicular development to maturity. Treatment of this condition depends on adding injectable FSH to maintain proper follicular development or giving Clomiphene Citrate to stimulate FSH release resulting in normal ovulation.
Ovulation Induction Alternatives for Women with Anovulation or Oligo-ovulation.
This drug, commercially known as Clomid or Serophene, is the first alternative for treating women with anovulation or with oligo-ovulation. This drug blocks the effects of estrogen throughout the body. Therefore, the pituitary gland detects that there are low levels of estrogen in the blood stream. The pituitary’s response to low estrogen levels is to increase the output of FSH in order to provide more stimulation to the follicles and thus produce more estrogen. From a clinical perspective this rise in FSH is very important since it is sufficient to stimulate the follicles to complete normal development and eventually ovulation.
Usually, in the first Clomiphene Citrate (CC) stimulated cycle, women who have ovulatory problems take one pill per day for five days on days five through nine of the menstrual cycle. However, this timing may be adjusted also for specific patients. In the absence of proper stimulation the dosage is systematically increased until the effective dose is determined. In some cases the dose may need to go as high as five pills per day. During the CC therapy the patient is monitored to determine if ovulation did occur. Basal body temperature and ovulation predictor kits (OPKs), are useful elements to determine the mid-cycle surge of LH. The OPKs have the added advantage of turning positive prior to ovulation which allows a more precise timing of intercourse or insemination. The ultimate test for ovulation is determining blood progesterone levels five to ten days later. This test not only confirms that ovulation took place but also it may reaffirm that progesterone support, during the second half of the cycle, is adequate.
Most of the pregnancies will occur in the first three CC stimulated cycles and very few pregnancies will be achieved beyond the sixth ovulatory cycle. Therefore, it is recommended to have no more than three CC stimulated cycles and change to gonadotropin induced cycles in subsequent attempts. Clinical research has shown that combining CC therapy with intrauterine insemination will increase the odds of pregnancy. With proper monitoring and stimulation five to ten percent of the pregnancies will be twins. In some cases, higher order pregnancies (triplets or more) may occur if not followed properly.
Some of the side effects of CC therapy are associated with the “artificial” blockage of estrogen’s favorable effects on mucus production by the cervix. In some cases, the treatment may result in a hostile environment for the sperm reaching the site of fertilization after intercourse. This problem may be averted with intrauterine insemination. In other cases, due to the blockage, the endometrium may not be receptive for implantation. Therefore, pregnancy rates are lower, even with IUI, than injectable gonadotropin therapy. Other side effects include hot flashes, upset gastrointestinal tract, headaches, visual disturbances, mood swings and breast tenderness. As indicated earlier, the major side effect of CC therapy is the probability of a high order pregnancy.
Some women who do not respond or do not get pregnant following CC therapy will be considered for injectable gonadotropins. The gonadotropin hormones or gonadotropins are FSH and LH. In the past, these two hormones were isolated from urine of post-menopausal women, which is why they were also known as Urofollitropins. They contained roughly about 50% of each hormone. It was felt that there were larger amounts of LH than was physiologically needed. FSH products with lower LH content (5% or less) were introduced later. Recently, pure FSH preparations produced by DNA recombinant technologies were placed on the market. It is not clear yet if the lack of LH in the FSH injections will have a positive impact on the general population using these compounds. However, it is clinically significant to use low or no LH contaminated FSH compounds in specific cases such as patients with poly-cystic ovarian syndrome.
The rise of FSH observed with CC therapy may not be large enough to provide sufficient stimulation to achieve ovulation and pregnancy. In a number of cases, women will respond better if higher and sustained levels of FSH can be obtained. Exogenous gonadotropins will work in the majority of cases where CC therapy did not. The goal of any form of ovarian stimulation is to achieve the development of a single follicle. However, the response of patients to the gonadotropins is very diverse and often associated to patient’s age, number of follicles in the ovaries, presence of genetic or endocrine conditions. Fortunately, a number of different stimulation protocols have been described. Low doses of FSH given for a long period of time (“low and slow protocols”) are recommended for patients with a very large number of small follicles. Those with lesser numbers of follicles may require a more aggressive approach with larger amounts of FSH to achieve a similar ovarian response. In general, the medication is administered for a period of 7-12 days. In rare cases a single follicle develops. Most of the time several follicles mature and release eggs for fertilization. This may lead to a high incidence of multiple pregnancies if proper monitoring and actions are not in place. Close evaluation of blood estrogens and ovarian ultrasound monitoring must be a standard practice to avoid hyperstimulation.
Ovarian Stimulation for Normal Women.
Some patients who are ovulating normally may also be subjected to treatment with exogenous gonadotropins in order to increase the probability of pregnancy by increasing the number of eggs in cases of male factor infertility or when IUIs are given. These patients may have an excessive response to FSH. Therefore, it will never be overemphasized to stick to a strict monitoring protocol to reduce the probability of a multiple pregnancy. Cancellation of IUI or selective reduction is also used to avoid multiple pregnancies. The first cycle should be started with the minimum dose and cautiously increase it in subsequent cycles.
Ovarian Simulation for IVF Patients.
Most patients undergoing ovarian stimulation for IVF or related advanced reproductive technologies have their ovaries stimulated with gonadotropins. While the medications are the same as those used in the treatment of ovulatory dysfunctions, the objectives are quite different. The goal is to induce the development of several follicles at the same time. Higher FSH doses are typically prescribed and it is necessary to monitor estrogen levels and follicle development to avoid excessive growth and ovarian hyper-stimulation syndrome.
Other Hormones Used In Ovulation Induction Cycles With Gonadotropins.
It is possible to use FSH only to induce follicular growth and ovulation in most patients. However, it would be necessary to monitor the mid-cycle LH surge that precedes ovulation for proper timing of intercourse or IUIs and this could potentially represent a logistical problem. Drugs such as GnRH (Lupron) and hCG can be used to have more control on the stimulated cycle. While Lupron does not affect the normal follicular growth during FSH treatment, it inhibits the spontaneous preovulatory mid-cycle LH surge. A hormone, hCG, with LH effect may be administered so ovulation will occur at a more convenient time for the patient to receive adequate care. The mid-cycle LH surge or the hCG injections not only are important to induce ovulation but also they will induce the final maturation steps prior to fertilization.
More on Proper Monitoring.
Close monitoring of women being treated with injectable reproductive hormones is an important aspect of patient care. The intra-ovarian control mechanisms leading to a single ovulation during the FSH treatment are bypassed and a larger crop of follicles are recruited. The objective of monitoring is to make sure that a moderate, not excessive, ovarian response is obtained. Proper monitoring involves a combination of ultrasounds (that determines the number and size of the follicles and helps to diagnose when the follicles are mature and ready to ovulate and when the hCG should be given) and blood estrogen levels. The information obtained, number and size of follicles growing, rate of development and estrogen levels help the physician to adjust the dosage of the medication being administered. Proper monitoring would not only help to optimize the probability of pregnancy but also it would save you from serious complications in case you experience an excessive response to the treatment. See “FSH Side Effects” later.
Factors Affecting the Probability of Success.
Most women injected with FSH and other reproductive hormones will experience ovulation. However, not all of them will conceive. The highest probability of pregnancy will be during the first six cycles. Among the factors influencing success include: age, number of follicles in the ovaries, endometriosis or other pelvic inflammatory conditions, cervical or endometrial factors and sperm quality. Other factors such as chromosomal imbalances, immunological conditions, etc. may have an impact on infertility. However, their prevalence is low in the general population.
Side Effects of Ovulation Induction Treatments.
Minor conditions. Soreness, discomfort, redness or bruising may appear at the site of injection when administering gonadotropins. Some patients will experience a feeling of abdominal fullness or bloating as the follicles in the ovaries enlarge as a result of the stimulation protocol. Fluid retention, mild nausea and headaches are some other side effects. High Order Pregnancies. There is a high risk of multiple pregnancies when proper care is not followed during an ovarian stimulation cycle. Results indicate that about 70% of the pregnancies obtained with ovarian stimulation protocols result in singletons, about 20% in twins, 5% triplets and the rest include quadruplets or higher order pregnancies which require, in most cases, selective reduction to preserve health and safety of the mother and any other remaining fetuses. Another approach is to cancel insemination if too many follicles appear to be ready to ovulate. Pregnancies with triples or more fetuses not only are very expensive but also they may results in permanent damage to the mother or the babies being produced reducing their ability to enjoy and succeed in life. They can be reduced with proper medical monitoring. Ovarian Hyper Stimulation Syndrome. This is unique to ovulation induction cycles and is the result of an excessive response to the gonadotropins. More than 15-20 follicles develop producing high levels of estrogen in the blood. The estrogen is responsible for fluid retention in the abdomen or other parts of the body. The symptoms begin about a week after ovulation and it is further complicated if the woman gets pregnant. In severe cases these women may experience nausea, excessive weight gain, and they may require close monitoring and treatment. The symptoms may go away in a week or two. These problems may be reduced, not totally eliminated, with proper monitoring BEFORE ovulation.