Treatment Options
Content
Treatment Options A. Gonadotropin Therapy
y y Purpose: stimulate ovarian follicular development or induce ovulation. Method: giving exogenous gonadotropins supplement or replace the woman's own gonadotropins give hCG if follicle grow to certain size (to promote oocyte maturation, induce ovulation, and allow appropriate corpus luteum formation and function). y Functional ovarian tissue is required for successful treatment. y A baseline transvaginal ultrasound is performed before gonadotropin injections begun to identify uterine abnormalities such as endometrial polyps, submucosal fibroids, or congenital defects. y Contraindications of Gonadotropins for the Treatment of Infertility in Women: 1. Primary ovarian failure with elevated follicle²stimulating hormone levels 2. Uncontrolled thyroid and adrenal dysfunction 3. An organic intracranial lesion such as a pituitary tumor 4. Undiagnosed abnormal uterine bleeding 5. Ovarian cysts or enlargement not caused by polycystic ovary syndrome 6. Prior hypersensitivity to the particular gonadotropin 7. Sex hormone²dependent tumors of the reproductive tract and accessory organs 8. Pregnancy Starting Dose of Gonadotropin y Gonadotropin dosages can be administered every evening, allowing morning measurements of serum estradiol to reflect the steady state. If the patient has had previous gonadotropin treatment, the starting dose should be based on review of ovarian response in previous cycles. y Patients with hypogonadotropic hypogonadism usually begin with 75 IU per day.
Monitoring and Adjustment of Dosage
y The dose of gonadotropins is maintained until day 6 or 7, when the serum estradiol level is first measured to document ovarian response. Transvaginal ultrasound also is performed at this time to determine follicular response. If these measurements detect no response, the gonadotropin dosage is increased by 50 to 100 IU per day every 2 to 4 days until a response is evident by rising estradiol levels (or until the maximal dosage is reached). The maximal dosage is usually 450 IU per day because higher dosages usually do not increase ovarian response Once an ovarian response is obtained, treatment typically is continued without further increase in dose. When the largest measured follicle reaches a maximum diameter of 18 to 19 mm or more, 10,000 IU of hCG (Profasi) is administered intramuscularly. Alternatively, recombinant hCG (Ovidrel) can be given at 250 g subcutaneously. Optimal pregnancy rates are achieved at 33 to 39 hours after the hCG injection. If menses does not occur after a treatment cycle, testing for pregnancy should be performed about 15 to 16 days after hCG administration. If pregnancy does not occur, the cycle should be reviewed. If appropriate follicle size, number, and estradiol levels have been reached, there is no need to change the gonadotropin dosage.
y
y
Human Chorionic Gonadotropin Administration
y
Pregnancy Test or Plans for Next Cycle
y y
B.
y y
Assisted Reproductive Technologies
Purpose: interventions to retrieve oocytes. Techniques
1. IVF and ICSI 2. gamete intrafallopian transfer (GIFT) 3. zygote intrafallopian transfer (ZIFT) 4. cryopreserved embryo transfers 5. use of donor oocytes. The typical ART cycle (IVF or ICSI) has the following main components:. a. Using gonadotropins, follicular development monitoring with transvaginal ultrasound, and assessment of serum estradiol levels. b. Prevention of premature LH surge and ovulation. c. Oocyte maturation using hCG. d. Oocyte retrieval. e. Fertilization by IVF or ICSI. f. In vitro embryo culture. g. Luteal support or endometrial preparation using progesterone supplementation. h. Transfer of fresh embryos with possible cryopreservation of excess embryos. i. First²trimester pregnancy monitoring.
Prevention of Premature Luteinizing Hormone Surge/Ovulation
y The use of GnRH agonist has become standard in ART protocols to prevents spontaneous ovulation, decreases treatment complications, and allows the control of ovulation to rest exclusively on administration of exogenous medications. GnRH agonists induces a quiescent hypothalamic²pituitary²ovarian axis and a menopauselike state characterized by low estradiol levels. The most commonly used regimen for superovulation in ART is called the long, or luteal, downregulation protocol. The benefits of using the long protocol for administration of GnRH agonists greatly outweigh its disadvantages, which include daily administration, increased requirement for gonadotropins, and an overall increase in the cost of medication. In a meta²analysis reviewing the efficacy of various GnRH agonist regimens, the authors concluded that the addition of GnRH agonist downregulation to ovulation induction regimens for ART was advantageous. Currently, the long GnRH agonist protocol is generally recommended for most patients, and use of the short protocol in ART patients with poor ovarian response has not been proved beneficial.
y y y
y
hCG Injection
y
The injection of hCG induces oocyte maturation before retrieval. The dosage of hCG typically is 10,000 IU given intramuscularly or subcutaneously, or 250 g recombinant hCG given subcutaneously. Performed 35 hours after the hCG injection. Although historically performed by laparoscopy, laparoscopic oocyte retrieval has now been replaced by the transvaginal ultrasound ²guided approach. Transvaginal ultrasound²guided retrieval is markedly less invasive than its laparoscopic counterpart, and the use of ultrasound permits the surgeon to visualize the location of the needle within each ovarian follicle. Fertilization of the human oocyte by human sperm in vivo requires the interaction of capacitated spermatozoa with ovulated oocytes. Capacitation of sperm takes place in the female reproductive tract and involves both changes in sperm motility and changes in the sperm cell membrane that allow the acrosome reaction. The mandate of the ART team is to attempt to recreate precisely those processes known to occur in unassisted conception.
Oocyte Retrieval
y y
IVF and ICSI
y y
y
Luteal Support y Usually initiated on the day after oocyte retrieval for ART. Commonly used regimens include
the following:. 1. Progesterone in oil 50 mg, once a day, intramuscularly. 2. Vaginal progesterone suppositories, 200 mg twice to three times a day. 3. Oral micronized progesterone, 200 mg twice a day.
y
Despite similar levels of circulating progesterone, the oral regimen is associated with decreased per²embryo implantation rates when compared with use of intramuscular progesterone.
Embryo Transfer y In unassisted conception, the fertilized oocyte traverses through the fallopian tube for 2 to 3
days before entry into the uterus for implantation.
y
The embryo resides in the intrauterine cavity for 2 to 3 days before implantation. During this period, the zona pellucida detaches, allowing implantation to occur 5 to 7 days after fertilization. Pregnancy rates resulting from blastocyst transfer range between 44% for low² scoring blastocysts and 87% for top²scoring ones. The success of modern ovulation induction and fertilization regimens often results in embryos in excess of the number appropriate for transfer in a single treatment cycle. Cryopreservation of these embryos permits embryo transfer to the same patient in unstimulated cycles in the future. Some patients receive cryopreserved embryos during ´naturalµ cycles, whereas other patients undergo endometrial preparation with sequential administration of exogenous estrogen and progesterone. Pregnancies resulting from transfer of cryopreserved embryos effectively reduce the costs of pregnancy per ovulation stimulation. Conversely, in cryopreserved cycles, not all embryos survive thawing, and the pregnancy rates are lower than those using fresh embryos. Serial quantitative hCG levels may be obtained starting on day 16 after oocyte retrieval. Serum hCG levels taken earlier than this day may give false²negative or false²positive results. A single serum progesterone level on day 16 does not provide further prognostic value and is therefore not recommended. Patients usually undergo serial serum hCG level assessment early in pregnancy, followed by transvaginal ultrasound at 5 to 6 weeks of gestation to document intrauterine location of the pregnancy and the number of gestational sacs. This is especially important for patients with risk factors for ectopic pregnancy, those who are experiencing vaginal bleeding, and those at high risk for higher ²order multiple gestation. Transvaginal ultrasound at 7 to 8 weeks for identification of fetal cardiac activity can provide further reassurance..
y
Cryopreservation of Embryos
y y
y
Pregnancy Testing and Follow²up of Early Pregnancy
y y y y
y y
C.
y
Treatment with Donor Oocytes
Women with premature ovarian failure have very few reproductive options. The use of donor oocytes may represent the only proven method by which most of these patients can become pregnant. Other patients to be considered for donor oocyte technology may include those with poor oocyte quality (including some patients with failed fertilization), those with poor ovarian response to stimulation, and those with a history of multiple failed ART cycles. Like semen donors, potential oocyte donors must be stringently assessed, including screening for transmittable infectious or genetic diseases. Unlike semen, however, oocytes cannot presently be cryopreserved and quarantined.
y
y
y
Considerable coordination is required to ensure that the recipient's endometrium is appropriately prepared when embryos freshly fertilized from the donor oocytes are ready to be transferred. To ensure adequate endometrial preparation, many recipients of donor oocytes are taken through a ´mockµ cycle before their actual treatment cycle. During the mock cycle, all hormonal agents are administered, and endometrial adequacy is documented by timed endometrial biopsies.
y y Purpose: stimulate ovarian follicular development or induce ovulation. Method: giving exogenous gonadotropins supplement or replace the woman's own gonadotropins give hCG if follicle grow to certain size (to promote oocyte maturation, induce ovulation, and allow appropriate corpus luteum formation and function). y Functional ovarian tissue is required for successful treatment. y A baseline transvaginal ultrasound is performed before gonadotropin injections begun to identify uterine abnormalities such as endometrial polyps, submucosal fibroids, or congenital defects. y Contraindications of Gonadotropins for the Treatment of Infertility in Women: 1. Primary ovarian failure with elevated follicle²stimulating hormone levels 2. Uncontrolled thyroid and adrenal dysfunction 3. An organic intracranial lesion such as a pituitary tumor 4. Undiagnosed abnormal uterine bleeding 5. Ovarian cysts or enlargement not caused by polycystic ovary syndrome 6. Prior hypersensitivity to the particular gonadotropin 7. Sex hormone²dependent tumors of the reproductive tract and accessory organs 8. Pregnancy Starting Dose of Gonadotropin y Gonadotropin dosages can be administered every evening, allowing morning measurements of serum estradiol to reflect the steady state. If the patient has had previous gonadotropin treatment, the starting dose should be based on review of ovarian response in previous cycles. y Patients with hypogonadotropic hypogonadism usually begin with 75 IU per day.
Monitoring and Adjustment of Dosage
y The dose of gonadotropins is maintained until day 6 or 7, when the serum estradiol level is first measured to document ovarian response. Transvaginal ultrasound also is performed at this time to determine follicular response. If these measurements detect no response, the gonadotropin dosage is increased by 50 to 100 IU per day every 2 to 4 days until a response is evident by rising estradiol levels (or until the maximal dosage is reached). The maximal dosage is usually 450 IU per day because higher dosages usually do not increase ovarian response Once an ovarian response is obtained, treatment typically is continued without further increase in dose. When the largest measured follicle reaches a maximum diameter of 18 to 19 mm or more, 10,000 IU of hCG (Profasi) is administered intramuscularly. Alternatively, recombinant hCG (Ovidrel) can be given at 250 g subcutaneously. Optimal pregnancy rates are achieved at 33 to 39 hours after the hCG injection. If menses does not occur after a treatment cycle, testing for pregnancy should be performed about 15 to 16 days after hCG administration. If pregnancy does not occur, the cycle should be reviewed. If appropriate follicle size, number, and estradiol levels have been reached, there is no need to change the gonadotropin dosage.
y
y
Human Chorionic Gonadotropin Administration
y
Pregnancy Test or Plans for Next Cycle
y y
B.
y y
Assisted Reproductive Technologies
Purpose: interventions to retrieve oocytes. Techniques
1. IVF and ICSI 2. gamete intrafallopian transfer (GIFT) 3. zygote intrafallopian transfer (ZIFT) 4. cryopreserved embryo transfers 5. use of donor oocytes. The typical ART cycle (IVF or ICSI) has the following main components:. a. Using gonadotropins, follicular development monitoring with transvaginal ultrasound, and assessment of serum estradiol levels. b. Prevention of premature LH surge and ovulation. c. Oocyte maturation using hCG. d. Oocyte retrieval. e. Fertilization by IVF or ICSI. f. In vitro embryo culture. g. Luteal support or endometrial preparation using progesterone supplementation. h. Transfer of fresh embryos with possible cryopreservation of excess embryos. i. First²trimester pregnancy monitoring.
Prevention of Premature Luteinizing Hormone Surge/Ovulation
y The use of GnRH agonist has become standard in ART protocols to prevents spontaneous ovulation, decreases treatment complications, and allows the control of ovulation to rest exclusively on administration of exogenous medications. GnRH agonists induces a quiescent hypothalamic²pituitary²ovarian axis and a menopauselike state characterized by low estradiol levels. The most commonly used regimen for superovulation in ART is called the long, or luteal, downregulation protocol. The benefits of using the long protocol for administration of GnRH agonists greatly outweigh its disadvantages, which include daily administration, increased requirement for gonadotropins, and an overall increase in the cost of medication. In a meta²analysis reviewing the efficacy of various GnRH agonist regimens, the authors concluded that the addition of GnRH agonist downregulation to ovulation induction regimens for ART was advantageous. Currently, the long GnRH agonist protocol is generally recommended for most patients, and use of the short protocol in ART patients with poor ovarian response has not been proved beneficial.
y y y
y
hCG Injection
y
The injection of hCG induces oocyte maturation before retrieval. The dosage of hCG typically is 10,000 IU given intramuscularly or subcutaneously, or 250 g recombinant hCG given subcutaneously. Performed 35 hours after the hCG injection. Although historically performed by laparoscopy, laparoscopic oocyte retrieval has now been replaced by the transvaginal ultrasound ²guided approach. Transvaginal ultrasound²guided retrieval is markedly less invasive than its laparoscopic counterpart, and the use of ultrasound permits the surgeon to visualize the location of the needle within each ovarian follicle. Fertilization of the human oocyte by human sperm in vivo requires the interaction of capacitated spermatozoa with ovulated oocytes. Capacitation of sperm takes place in the female reproductive tract and involves both changes in sperm motility and changes in the sperm cell membrane that allow the acrosome reaction. The mandate of the ART team is to attempt to recreate precisely those processes known to occur in unassisted conception.
Oocyte Retrieval
y y
IVF and ICSI
y y
y
Luteal Support y Usually initiated on the day after oocyte retrieval for ART. Commonly used regimens include
the following:. 1. Progesterone in oil 50 mg, once a day, intramuscularly. 2. Vaginal progesterone suppositories, 200 mg twice to three times a day. 3. Oral micronized progesterone, 200 mg twice a day.
y
Despite similar levels of circulating progesterone, the oral regimen is associated with decreased per²embryo implantation rates when compared with use of intramuscular progesterone.
Embryo Transfer y In unassisted conception, the fertilized oocyte traverses through the fallopian tube for 2 to 3
days before entry into the uterus for implantation.
y
The embryo resides in the intrauterine cavity for 2 to 3 days before implantation. During this period, the zona pellucida detaches, allowing implantation to occur 5 to 7 days after fertilization. Pregnancy rates resulting from blastocyst transfer range between 44% for low² scoring blastocysts and 87% for top²scoring ones. The success of modern ovulation induction and fertilization regimens often results in embryos in excess of the number appropriate for transfer in a single treatment cycle. Cryopreservation of these embryos permits embryo transfer to the same patient in unstimulated cycles in the future. Some patients receive cryopreserved embryos during ´naturalµ cycles, whereas other patients undergo endometrial preparation with sequential administration of exogenous estrogen and progesterone. Pregnancies resulting from transfer of cryopreserved embryos effectively reduce the costs of pregnancy per ovulation stimulation. Conversely, in cryopreserved cycles, not all embryos survive thawing, and the pregnancy rates are lower than those using fresh embryos. Serial quantitative hCG levels may be obtained starting on day 16 after oocyte retrieval. Serum hCG levels taken earlier than this day may give false²negative or false²positive results. A single serum progesterone level on day 16 does not provide further prognostic value and is therefore not recommended. Patients usually undergo serial serum hCG level assessment early in pregnancy, followed by transvaginal ultrasound at 5 to 6 weeks of gestation to document intrauterine location of the pregnancy and the number of gestational sacs. This is especially important for patients with risk factors for ectopic pregnancy, those who are experiencing vaginal bleeding, and those at high risk for higher ²order multiple gestation. Transvaginal ultrasound at 7 to 8 weeks for identification of fetal cardiac activity can provide further reassurance..
y
Cryopreservation of Embryos
y y
y
Pregnancy Testing and Follow²up of Early Pregnancy
y y y y
y y
C.
y
Treatment with Donor Oocytes
Women with premature ovarian failure have very few reproductive options. The use of donor oocytes may represent the only proven method by which most of these patients can become pregnant. Other patients to be considered for donor oocyte technology may include those with poor oocyte quality (including some patients with failed fertilization), those with poor ovarian response to stimulation, and those with a history of multiple failed ART cycles. Like semen donors, potential oocyte donors must be stringently assessed, including screening for transmittable infectious or genetic diseases. Unlike semen, however, oocytes cannot presently be cryopreserved and quarantined.
y
y
y
Considerable coordination is required to ensure that the recipient's endometrium is appropriately prepared when embryos freshly fertilized from the donor oocytes are ready to be transferred. To ensure adequate endometrial preparation, many recipients of donor oocytes are taken through a ´mockµ cycle before their actual treatment cycle. During the mock cycle, all hormonal agents are administered, and endometrial adequacy is documented by timed endometrial biopsies.
