by F. Nicholas Shamma, MD
Ovulation occurs in the woman each month due to a number of hormonal and anatomical changes. Several parts of your body are involved in the process of ovulation. The brain sends hormonal signals telling the ovaries to produce an egg each month. A hormone called gonadotropin releasing hormone (GnRH), which is produced in an area of the brain called the hypothalamus, acts on the pituitary gland to produce follicle stimulating hormone (FSH) and luteinizing hormone (LH). These two hormones then act on the ovaries to help produce the growth and development of an egg in a process called ovulation.
Women are born with a finite number of eggs. At birth, a woman has around 1 to 2 million eggs. However, throughout her life, a woman loses eggs through a destructive process called atresia. At puberty, only around 400,000 eggs remain. Throughout the reproductive lifespan, from puberty until menopause, women lose about 1,000 eggs each month.
Of these thousand eggs, only one is released. Once released, it is picked up by the fallopian tube. If a couple has sexual intercourse around this time, fertilization (the joining of the egg and sperm) may take place. The fertilized egg, called an embryo, finds its way to the uterus where it gets implanted in the uterine wall and develops into a fetus. The fetus develops over a period of about nine months and, if all goes well, a healthy, happy baby is delivered.
Ovulation induction is a process whereby -- through drug therapy -- some of the 1,000 eggs lost monthly are rescued from atresia and allowed to develop to maturity. The following discussion is a description of the process of ovulation induction.
When is Ovulation Induction Used?
There are various reasons why a woman might need to undergo ovulation induction. Though the goal is always to promote ovulation, the treatment itself changes depending upon the woman's particular situation.
Some women are given medications to replace some or all of the hormones that are produced by the pituitary gland. Such a situation occurs when a woman has had surgery on the pituitary gland, or more commonly has a pituitary gland that is unable to produce the hormones FSH and LH. This latter scenario may happen when a woman loses a significant amount of weight in a condition known as anorexia nervosa. It also may occur when women exercise excessively or are under a considerable amount of psychological stress. Under these conditions, although the pituitary gland is normal, it does not produce FSH and LH. All of these circumstances fall under the category of ovarian dysfunction called hypothalamic-pituitary dysfunction.
Several hormonal treatments are currently available to women who cannot produce FSH and LH. These medications are called gonadotropins. These gonadotropins are given by injection either into the muscle or under the skin. Two major forms of these medications are currently available. One form contains an equal amount of FSH and LH. This medication is available in the United States under the trade names Humegon, Pergonal, or Repronex. These forms, which contain LH and FSH extracted from the urine of postmenopausal women, are usually given by injection into the muscle. The other form of this medication is a newly developed product made of genetically engineered FSH. This medication is available in the United States under the trade name of Gonal F or Follistim. This product can be injected under the skin, a much easier and much less painful way of administering the medication.
With gonadotropin therapy, you usually start the medication on the third day of the menstrual cycle, with day 1 representing the first day of the menstrual bleeding. The medication is continued for an average of 10 days. During this period, ultrasound examinations of the ovaries are regularly performed to monitor the growth of the follicles. The follicle is the structure within which the human egg, or oocyte, develops. When it is determined by ultrasound that the follicles have reached maturity, the final trigger of ovulation, human chorionic gonadotropin or hCG, is given to release the eggs. Because this process involves the release of multiple eggs, more than one egg may be picked up by the fallopian tube, and fertilized. If all of these implant, it would result in a multiple gestation, i.e. twins, triplets, or even more.
There is another ovulation induction regimen that can be utilized by women who are experiencing hypothalamic-pituitary dysfunction. This involves utilizing a hormone known as GnRH. This hormone acts on the pituitary gland causing it to produce LH and FSH. This medication is either given in the vein (intravenously) or under the skin via a pump. The pump, however, is cumbersome and seldom used in the United States.
Polycystic ovarian syndrome
This is a more common syndrome in which the brain can produce FSH and LH, but the ovaries do not respond normally to these hormones, and therefore do not develop a mature egg each month. Doctors call the inability to produce an egg each month "chronic anovulation". Polycystic ovarian syndrome usually occurs in women who are overweight and have excess body hair, oily skin, and sometimes acne. Such women will not produce the ovarian hormones estrogen and progesterone which are necessary for the uterus to produce a menstrual period each month. As a result, they have long and irregular menstrual cycles or no menstrual periods whatsoever. One of the recent advances in polycystic ovarian syndrome is the finding that some of the women with this syndrome have a high insulin level in their blood, a condition known as hyperinsulinemia. This is due to an inability of the body's insulin to work effectively (called "insulin resistance").
In women who have polycystic ovarian syndrome, an oral medication called clomiphene citrate is sometimes given to enhance ovulation. This medication acts on the brain resulting in the release of FSH, which in turn acts on the ovary resulting in the development of one or more follicles (see above). Clomiphene citrate is usually started on day three to five of the menstrual cycle and continued for 5 to 7 days. The usual therapy starts with one 50 mg pill daily for five days starting on the third day of the menstrual cycle. Ovulation occurs 5 to 10 days after taking the last pill. If the woman does not have a menstrual period after taking clomiphene citrate, she is either pregnant or did not ovulate. If she did not ovulate, the dose of the medication is increased to two pills daily for 5 days in a later menstrual cycle. This may be continued to a maximum daily dose of 250 milligrams.
Determining if ovulation has occured can sometimes be tricky. This may either be done by performing an ultrasound around mid-cycle, and observing that one or more follicles are developing, or by measuring blood progesterone level a week after the presumed date of ovulation. Body temperature charts which show an elevation of 0.5 degrees Fahrenheit or more for several days can also suggest that ovulation has occurred. In addition, ovulation prediction kits utilizing urine specimens can accurately determine ovulation. Because only approximately 50 percent of patients with polycystic ovarian syndrome eventually ovulate, these patients sometimes have to resort to more intense therapy utilizing injectable gonadotropins. As mentioned above, such therapy involves utilizing injectable rather than oral medications, and is significantly more expensive. Several other forms of therapy are occasionally utilized in women who fail to ovulate following clomiphene citrate or gonadotropins. Metformin is occasionally used in women with insulin resistance. Occasionally, steroids are used to lower the increased male hormones that are sometimes encountered in women with polycystic ovarian syndrome.
Endocrine (glandular) disorders
Women with hypothyroidism (low thyroid) are treated with thyroid replacement. Such therapy usually corrects any ovulatory dysfunction. Women with milky breast discharge from both breasts and hyperprolactinemia (increased prolactin hormone) can be adequately treated with medications to lower their prolactin level. Lowering the prolactin usually results in spontaneous ovulation and eventually pregnancy.
In Vitro Fertilization
Ovulation induction is also used during in vitro-fertilization (IVF). In this case, women who are having trouble conceiving undergo a process called controlled ovarian hyperstimulation (COH) in order to produce multiple eggs. These are removed from the ovaries and then fertilized by sperm in a laboratory dish before being placed in the uterus.
Women undergoing IVF usually utilize injectable gonadotropins to enhance ovulation. In IVF, the gonadotropins produce multiple follicles, which, when they are mature, are aspirated via the vagina and fertilized in the laboratory. This allows production of multiple embryos, which later can be transferred to the fallopian tube or uterus, resulting hopefully in implantation and pregnancy. There are multiple strategies for IVF. Most of these utilize birth control pills followed by a medication known as GnRH-agonist available in United States under the trade name Lupron or Synarel. This medication puts a woman in a temporary menopause-like state allowing her physician to control the timing of ovulation. This is then followed by the use of the gonadotropins mentioned above. Because GnRH-agonists cause temporary menopause, they are oftentimes associated with hot flashes, vaginal dryness, memory changes, and headaches.
Similarly, ovulation induction is also utilized in egg donation, a process where a woman may produce multiple eggs to donate to another woman.
Success Rates of Ovulation Induction
Ovulation induction utilizing gonadotropins can result in a conception rate of around 80 to 90 percent in women with hypothalamic-pituitary dysfunction after six treatments cycles. In women with polycystic ovarian syndrome, pregnancy rates are slightly lower. Miscarriage rates are around 15 to 20 percent in patients with hypothalamic-pituitary dysfunction. They are higher in women with polycystic ovarian syndrome.
Success rates of women undergoing COH or IVF depend on a number of factors, including whether or not there is a sperm dysfunction in the male partner, or a disease of the fallopian tubes. However, the most important factor determining the success rate of ovulation induction remains the age of the female patient. This is due to a increased genetic abnormalities in a woman's eggs as she grows older. This fact is also reflected in the higher miscarriage rates that occur in older women. Currently most good IVF programs have an approximately 30 percent delivery rate following IVF, and 20 percent following COH.
Ovulation occurs in 80 percent of women with polycystic ovarian syndrome who are using clomiphene citrate (see above). However, as has been mentioned, only 40 to 50 percent of women will eventually conceive. The success rates are higher in women without any other fertility problem. Therefore, it is possible to reach a cumulative pregnancy rate of 75 percent in six months of the therapy. Most of those pregnancies occur in the first three months of the use of the medication, and very few occur after six months. As a result, the use of clomiphene citrate is usually limited to six months of therapy.
Side Effects of Ovulation Induction
Multiple pregnancy occurs in around five percent of patients taking clomiphene citrate. Very few patients will have more than twins. However, multiple pregnancy rates are higher in women taking gonadotropins, frequently reaching 20 to 30 percent. Triplets and higher order pregnancies occur in 2 to 3 percent or less of pregnancies following the use of gonadotropins.
By closely monitoring women, physicians may be able to detect the number of the developing follicles and therefore control to some degree the multiple pregnancy rate. Most women have to be counseled ahead of time about the risk of multiple pregnancy to not only the mother, but also the fetus. Multiple pregnancy fetuses are at risk of prematurity and possible long-term disability.
Clomiphene citrate and gonadotropins can result in symptoms related to ovarian enlargement. Abdominal distension and discomfort may occur as can breast tenderness. Occasionally, women taking clomiphene citrate experience hot flashes. Other side effects include headaches, visual disturbances, and mood swings.
Ovarian hyperstimulation syndrome is another side effect that a woman might experience. It is a very serious and potentially lethal disorder. The incidence of ovarian hyperstimulation syndrome, also known as OHSS, is less than 3 to 5 percent of patients undergoing ovulation induction. It is much less common following clomiphene citrate than gonadotropin use.
OHSS involves enlargement of the abdomen and and accumulation of fluid in the abdomen and pelvis. It also is associated with nausea, vomiting, and difficulty breathing. Rarely, serious complications involving the liver, the kidney, and the lungs may occur. Because of the seriousness of this disorder, it is far better to prevent the occurrence of this syndrome than managing its consequences. Therefore, careful monitoring with ultrasound examinations and blood tests is crucial in assessing the risk of patients undergoing ovulation induction.
Finally, there is still debate on whether prolonged use of ovulation induction agents results in an increased risk of ovarian and breast cancer, though such a risk is minimal in women who eventually conceive and deliver.
I hope that this discussion has been helpful in answering some of your questions regarding ovulation induction. I strongly recommend that you ask your physician about his or her qualifications and board certification prior to commencing therapy, and discuss with him or her any concerns you might have.
Dr. Fayek Nicholas Shamma, board certified in Obstetrics and Gynecology and in Reproductive Endocrinology and Infertility, is the Associate Director of Ann Arbor Reproductive Medicine Associates, the Toledo Fertility Center, and the Mid-Michigan Fertility Center. He is also an assistant professor at Michigan State University College of Human Medicine. Dr. Shamma trained in Obstetrics and Gynecology at Yale New Haven Hospital in New Haven, CT, where he also went on to do sub-specialty training in Reproductive Endocrinology and Infertility. In his practice, Dr. Shamma takes care of patients with a variety of infertility problems. He routinely performs ovulation induction and in-vitro fertilization. He also performs other types of assisted reproductive procedures, including the use of donor eggs or embryos, the injection of sperm into female eggs, and the use of gestational surrogacy. As an infertility surgeon, he also performs various corrective surgeries related to infertility.
Dr. Shamma has written many articles in professional journals on the topics of infertility and in-vitro fertilization. He has also presented several studies in the area of ovulation induction and in-vitro fertilization at major national and international medical meetings.
Copyright © Fayek Nicholas Shamma. Permission to republish granted to Pregnancy.org, LLC.