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Advanced Infertility

After your comprehensive evaluation for the cause of infertility, the staff and doctor at the Center will advise you in the most appropriate treatment plan based on your special circumstances, religious beliefs and financial concerns. Usually the common treatments are ovulation induction and/or intrauterine insemination (IUI). The success rate with IUI is around 20% nationally. The Center with its unique treatment protocol tailored to the individual patient has attained a success rate of 46%. Artificial Insemination- IUI Ovulation Induction-OI

Ovulation Induction-OI

About Clomiphene (Serophene and Clomid) Clomiphene for Ovulation Induction Organs and Hormones Involved in Reproductive Function) Brief Review of Ovarian Function How Ovulation Induction with Reproductive Hormones May Help Infertile Patients

Ovulation induction is 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. The most common drug used is Clomid. If Clomid does not work injectable gonadotrophins are used.

About Clomiphene (Serophene and Clomid)...

To learn more about the therapy that often follows Clomiphene, go to our Exogenous (Injectable) Gonadotropin section.
The following pages will be helpful in understanding the Ovulation Induction (OI)process and function: Ovulation Induction.


Clomiphene for Ovulation Induction

Clomiphene Citrate
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 (Follicle Stimulating Hormone) 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 three through seven 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.

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 Gonadotropic Releasing Hormone (GnRH or commercially known as Factrel Direct), 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 cyst 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 histologic 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.

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 28th 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.

Brief Review of Ovarian Function

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, that 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 now why only one follicle is ovulated during a normal menstrual period.Some of the factors that interfere with the woman’s ability to conceive are those related to ovulatory dysfunction. 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.

How Ovulation Induction with Reproductive Hormones May Help Infertile Patients

Hypothalamic-Pituitary Problems. Failure to ovulate may be due in part to little or no stimulation coming from the pituitary gland. Insufficient LH and FSH to stimulate any follicles in the ovaries to maturity result in 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).

Ovarian Failure. 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.
Ovarian Cysts and Chronic Anovulation. 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. Recently the role insulin resistance has been demonstrated in certain patients with PCOS. 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.

Artificial Insemination- IUI

Clomiphene for Ovulation Induction

Intra-Uterine Insemination (IUI) and ovarian stimulation with exogenous hormones is the alternative with the highest probability of pregnancy for couples with infertility associated with specific diagnoses-directed treatments and those with unexplained infertility. IUI is the intra-uterine insemination of post-ejaculate, washed and activated sperm that is directly injected into the uterus with a soft catheter. IUI is the treatment of choice when adequate sperm concentrations are available and other female factors are not involved.

In general, Artificial Insemination (AI) involves placing sperm directly in the female reproductive tract of an infertile patient whose ovaries may or may not be stimulated with hormones. Intra-Uterine Insemination (IUI) and ovarian stimulation with exogenous hormones is the alternative with the highest probability of pregnancy for couples with infertility associated with specific diagnoses-directed treatments and those with unexplained infertility. However, since there are several alternatives and acronyms to describe them, depending on the specific clinical conditions of the couple, it may be difficult for the patient to distinguish one from another. The form of AI will be influenced by the effective sperm count, ovarian stimulation, sperm source (spouse or donor) and deposition of sperm in the female reproductive tract among others. Therefore, we intend to give a brief but general explanation of the different modalities associated with Artificial Insemination (AI), the clinical significance and the probability of pregnancy.



What is needed before AI?
 

Before AI is offered it is important to determine the cause(s) of infertility and a series of tests should be conducted to determine if the couple is a candidate for the procedure. A detailed medical history and physical examination should be conducted initially. The male partner will have two or more semen analysis and a few other tests conducted to estimate the fertilizing ability of his sperm. It is recommended that both be tested for HIV, hepatitis B and C, syphilis, gonorrhea, and chlamydia. In addition, the female partner should be evaluated for rubella and varicella immune status. Also, it is necessary to determine the time and frequency of ovulation using LH surge kits, basal body temperature (BBT) charts and cervical mucus examination. Some physicians may recommend a Post-coital Test but not much information can be gained from it. Some patients may need a hysterosalpingogram, hysteroscopy or laparoscopy prior to insemination to determine the status of the fallopian tubes, absence of severe adhesions in the pelvic cavity and a reproductive tract free of problems interfering with conception and pregnancy. If your medical history and pelvic exam suggests previous pelvic inflammatory diseases, infections, tubal damage, or endometriosis you will need at least one of those procedures.