Fertility may be restored by treatment of endocrine abnormalities, particularly hypothyroidism or hyperthyroidism. Women who are anovulatory as a result of low body weight or exercise may become ovulatory when they gain weight or decrease their exercise levels; conversely, obese women who are anovulatory may become ovulatory with loss of even 5–10% of body weight.
Excision of ovarian tumors or ovarian foci of endometriosis can improve fertility. Microsurgical relief of tubal obstruction due to salpingitis or tubal ligation will reestablish fertility in a significant number of cases, although with severe disease or proximal obstruction, IVF is preferable. Peritubal adhesions or endometriotic implants often can be treated via laparoscopy.
In a male with a varicocele, sperm characteristics may be improved following surgical treatment. For men who have sperm production but obstructive azoospermia, trans-epidermal sperm aspiration or microsurgical epidermal sperm aspiration has been successful.
C. Induction of Ovulation
Clomiphene citrate stimulates gonadotropin release, especially FSH. It acts as a selective estrogen receptor modulator, similar to tamoxifen and raloxifene, and binds to the estrogen receptor. The body perceives a low level of estrogen, decreasing the negative feedback on the hypothalamus, and there is an increased release of FSH and LH. When FSH and LH are present in the appropriate amounts and timing, ovulation occurs.
After a normal menstrual period or induction of withdrawal bleeding with progestin, clomiphene 50 mg orally should be given daily for 5 days, typically on days 3–7 of the cycle. If ovulation does not occur, the clomiphene dosage is increased to 100 mg orally daily for 5 days. If ovulation still does not occur, the course is repeated with 150 mg orally daily for 5 days and then 200 mg orally daily for 5 days. The maximum dosage is 200 mg orally daily. Ovulation and appropriate timing of intercourse can be facilitated with the addition of chorionic gonadotropin, 10,000 units intramuscularly. Monitoring of the follicles by transvaginal ultrasound is usually necessary to time the hCG injection appropriately. The rate of ovulation following this treatment is 90% in the absence of other infertility factors. The pregnancy rate is high. Twinning occurs in 5% of these pregnancies, but three or more fetuses are rare (less than 0.5% of cases). Pregnancy is most likely to occur within the first three ovulatory cycles, and unlikely to occur after cycle six. In addition, several studies have suggested a twofold to threefold increased risk of ovarian cancer with the use of clomiphene for more than 1 year, so treatment with clomiphene is usually limited to a maximum of six cycles.
The aromatase inhibitor letrozole appears to be at least as effective as clomiphene for induction of ovulation in women with PCOS. There is a reduced risk of multiple pregnancy, a lack of antiestrogenic effects, and a reduced need for ultrasound monitoring. The dose of letrozole is 5–7.5 mg daily, starting on day 3 of the menstrual cycle. In women who have a history of estrogen dependent tumors, such as breast cancer, letrozole is preferred over other agents because the estrogen levels with this medication are much lower.
If prolactin levels are elevated, an evaluation for a pituitary mass should be conducted. In the absence of a pituitary mass, cabergoline or bromocriptine may be used if prolactin levels are elevated and there is no withdrawal bleeding following progesterone administration (otherwise, clomiphene is used). The initial cabergoline dosage is 2.5 mg orally once daily, increased to 2.5 mg two or three times daily by 1.25 mg increments of cabergoline. The medication is discontinued once pregnancy occurs. Cabergoline causes fewer adverse effects than bromocriptine. However, it is much more expensive. Cabergoline is often used in patients who cannot tolerate the adverse effects of bromocriptine or who do not respond to bromocriptine.
4. Human menopausal gonadotropins (hMG) or recombinant FSH
hMG or recombinant FSH is indicated in cases of hypogonadotropism and most other types of anovulation resistant to clomiphene treatment. Because of the complexities, laboratory tests, and expense associated with this treatment, these patients should be referred to an infertility specialist.
D. Treatment of Endometriosis
E. Artificial Insemination in Azoospermia
If azoospermia is present, artificial insemination by a donor usually results in pregnancy, assuming female function is normal. The use of frozen sperm provides the opportunity for screening for sexually transmitted infections, including HIV infection.
F. Assisted Reproductive Technology (ART)
Couples who have not responded to traditional infertility treatments, including those with tubal disease, severe endometriosis, oligospermia, and immunologic or unexplained infertility, may benefit from ART. Gamete intrafallopian transfer and zygote intrafallopian transfer are rarely performed, although they may be an option in a few selected patients. These techniques are complex and require a highly organized team of specialists. All ART procedures involve ovarian stimulation to produce multiple oocytes, oocyte retrieval by transvaginal sonography–guided needle aspiration, and handling of the oocytes outside the body. With IVF, the eggs are fertilized in vitro and the embryos transferred to the uterus. Intracytoplasmic sperm injection allows fertilization with a single sperm. While originally intended for couples with male factor infertility, it is now used in two-thirds of all IVF procedures in the United States.
According to the CDC, ART accounts for approximately 1.7% of the total of US births. For women under the age of 35, over 50% of embryo transfers resulted in live birth compared to only about 4% for women age over 43. The chance of a multiple gestation pregnancy (ie, twins, triplets) is increased in all assisted reproductive procedures, increasing the risk of preterm delivery and other pregnancy complications. In 2017, approximately 35% of ART pregnancies were multiple, most of which (34%) were twins and only 1% were triplets. To minimize this risk, most infertility specialists recommend transferring only one embryo in appropriately selected patients with a favorable prognosis. In women with prior failed IVF cycles who are over the age of 40 who have poor embryo quality, up to four embryos may be transferred. In the event of a multiple gestation pregnancy, a couple may consider selective reduction to avoid the medical issues generally related to multiple births. This issue should be discussed with the couple before embryo transfer.