Medications

Lupron

Lupron is an injectable medication used to down-regulate the pituitary gland and prevent the release of substances such as Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). Without LH or FSH, the ovary will not produce follicles which will in turn decrease the production of Estrogen and Progesterone. When Lupron is discontinued, the body will resume normal production of FSH and LH.

In fertility treatment, this medication is primarily used during superovulation cycles. Daily exposure of Lupron reduces the chance of stray LH leakage into the bloodstream. In up to 30% of superovulation cycles without Lupron, spontaneous, premature LH surges can occur resulting in cycle cancellation. With Lupron down-regulation, this figure is reduced to less than 10%.

Lupron can also be used to cause medical menopause. The benefits of this condition come in the treatment of endometriosis, breast cancer, prostatic cancer and uterine fibroid tumors. Lowered estrogen levels tend to stem the progression of pathology and its associated pain. With endometriosis, the pain-free interval may be extended without frequent surgeries.

Prolonged usage to induce medical menopause will accelerate bone loss (osteoporosis) and increase the risk of coronary artery disease. After discontinuing Lupron, you may have an increased number of follicles, which increases your chance of multiple gestation.

Pergonal/Humegon/Metrodin/Clomiphene Citrate

Pergonal and Humegon consists of 75 IU of FSH (Follicle Stimulating Hormone) and 75 IU of LH (Luteinizing Hormone) per ampule by intramuscular injection. Metrodin is a similar injectable with 75 IU of purified FSH per ampule. Clomiphene is an anti-estrogen pill which causes the pituitary gland to secrete greater amounts of FSH. These drugs are used for women who are undergoing superovulation for the purpose of producing multiple eggs to induce and enhance ovulation or to use when undergoing assisted reproductive technologies such as IVF, GIFT, or ZIFT.

The potential risks of these drugs include hyperstimulation, a condition which may cause discomfort and/or require hospitalization, fluid replacement, plasma expanders, and daily aspiration of abdominal fluid. Multiple births occur at the rate of 15% for twins and 5% for triplets or greater. One study suggests Clomiphene usage may increase one's lifetime risk of ovarian cancer by 4.5%. Clean data is not available for Pergonal and Metrodin for risk of ovarian cancer, but some data does suggest an increase. Less than 1% of the time, the stimulated ovary can twist on itself, cutting off its own blood supply and requiring surgery to remove or untwist the ovary. In rare circumstances, arterial clots can occur, but most often accompany sever hyperstimulation. Venous clots are unpredictable, but there is a higher association with persons with history or family history of venous thrombosis or clotting disorder. Blood may also collect in the abdominal space from ruptured cysts.

The dosage of Pergonal or Metrodin varies from 1-6 ampules a day, intramuscularly for 7- 20 days. Monitoring of follicle response includes serial blood tests for estradiol levels and ultrasound measurement of follicle sizes and number.

Human Chorionic Gonadotropin (hCG)

HCG, also known by the trade name "Profasi", is a hormone which is naturally produced by the human placenta. The drug is used during superovulation cycles with Pergonal, Humegon, Metrodin, or Clomiphene citrate. HCG mimics the action of luteinizing hormone (LH) to signal or "trigger" egg maturation and release.

Precautions are headaches, irritability, depression, and pain at the site of the injection. When this is used with Pergonal or Metrodin in superovulation, it may potentiate the ovarian hyperstimulation syndrome.

Dosing for the trigger shot is typically 5,000 to 10,000 units given intramuscularly. Take the medicine on the hour instructed by the doctor, give or take 5 minutes.

Progesterone

Progesterone is the hormone produced by the corpus luteum following ovulation. Progesterone plays an important role in embryo implantation and the maintenance of early pregnancy. Progesterone supplementation is commonly employed when ovarian progesterone production is felt to be inadequate to initiate or maintain a pregnancy or to counterbalance the estrogen effect produced from multiple follicles developed during superovulation treatment.

Although the FDA has never approved the administration of progesterone in pregnancy, many studies have demonstrated the efficacy and relative safety of progesterone supplementation in these circumstances. Understand that progesterone is the same substance the ovary would normally make.

Side effects include lethargy, mood swings, depression and/or breast soreness. Progesterone may cause pain or irritation at the site of the injection when given intramuscularly. It may cause irritation of the vagina or perineum when given intravaginally.

Estrogen

We often recommend the use of estrogen supplementation to enhance uterine lining development and possibly increase the implantation rate and reduce the chance of miscarriage. This treatment is not a standard of care and estrogen supplementation during this process is controversial. We recommend the use of estrogens in the follicular development phase, then resumption 4-5 days after the surge or trigger. Normally, the estrogen drop follows the surge and slowly increases during the luteal phase. We attempt to mimic this phenomena.

Controversy over the use of estrogen supplementation in attempting pregnancy stems from the use of Diethylstilbesterol (DES), a synthetic estrogen used from the 40's through the 70's to treat complications of pregnancy which was later associated with fetal anomalies. Recent studies using estrogens that are closely related to those produced by the ovary (typically 17-beta estradiol) show no increase in fetal anomalies over the general population.

Primarily, we use estraderm patches as their bio-availability is greater than orally ingested estrogen and clinically the uterine lining appears better. In some patients with chronically low estrogens following ovulation, we have started them on injectable estradiol valerate. Again, both of these products are very similar to the estrogen produced by the ovary and have not been shown to produce fetal malformations.

Aspirin/Heparin/Prednisone

We recommend patients consider using baby aspirin, heparin, and possibly prednisone to help obtain and/or maintain a pregnancy. At the current time there is no published evidence for the use of these medicines to obtain or maintain pregnancy, except in the recurrent spontaneous miscarrier and the pregnancy with preeclampsia. Although no direct published evidence as to the benefit of aspirin, heparin, and prednisone to achieve pregnancy exists, their use is extrapolated from the work done in the recurrent miscarrier. The premise being that the unexplained infertile patient may be achieving fertilization and embryo development but the embryo fails to implant. In a sense, these patients may be early miscarriers.

We believe patients with endometriosis, Salpingitis isthmica nodosa, Hashimoto's thyroiditis, Raynoud's disease, lupus, rheumatoid arthritis, and other autoimmune disorders may initiate an antibody response that makes the mother's blood more hypercoaguable. The stress of pregnancy and the presence of the developing embryo activates the immune system to generate increased amounts of antiphospholipid antibodies (APA). These antibodies can attack phospholipids within mom's body. Free phospholipids are associated with hypercoagulation. If this is happening within the microvasculature of the placental-uterine interface, the developing embryo will die from lack of blood circulation. A major component of the placenta is phospholipids.

In a small experiment at Southwestern Medical School, blood that was positive for antiphospholipid antibodies was mixed with additional heparin and the APA test was repeated. The serum tested negative. The same serum was treated to remove heparin and APA was repeated and became positive. One explanation for this finding suggested that heparin may bind the APA and neutralize it to make it unable to be detected.

Pregnancy is considered a stress on the system which increases the level of circulating APA. Normal body heparin levels are not always adequate to keep the APA's from damaging the placenta. Our experience shows that 25-30% of recurrent miscarriers will not show positive APA's until they are tested during pregnancy.

Since the early implanting embryo does not require the larger blood flow of the 6 week gestation, why would hypercoagulation due to APA be a problems in early implantation? This question is an excellent one and one that we continue to struggle to answer. Obviously, hypercoagulation is not occurring early, but the APA may be associated with another immune problem. In a recent study of in vitro patients, the presence of APA significantly reduced the pregnancy outcome by half. In a small prospective trial, the patients were treated with a steroid during follicle development and the luteal phase in IVF and GIFT cycles. Those patients that did not have an APA, did not receive any benefit nor reduction in the pregnancy rates whether or not they took the steroid. In those patients who were APA positive and took the steroid, 8/10 got pregnancy; whereas, the group that declined the steroid, 0/25 were able to get pregnant. It is our observation that embryos from certain individuals will display fragmentation and we believe this is immunologically related.

A baby aspirin (81 mg) per day works in concert with heparin to improve clinical outcome. Aspirin in this dose is safe to the fetus, but should not be considered an innocuous drug. Avoid any other aspirin containing drugs such as Alka-seltzer, Pepto-Bismol, or non-steroidals like Advil or Anaprox. More than one baby aspirin can affect blood vessels in the fetus and cause them to narrow. This narrowing and potential closure can alter fetal blood flow and create low oxygen saturation. Low-blood oxygen, or hypoxia, can injure the fetal brain or other organs or cause fetal death.

Long-term heparin exposure is associated with increased bone loss. Pregnancy is a bone- losing situation, and the heparin only adds to the loss. Taking calcium does not appear to reverse the effect. The risk of a bone fracture is thought to be as high as 15%. The fracture could be as slight as a stress fracture in the hand or foot, to a vertebral crush fracture as seen in elderly postmenopausal women. Another risk is a drop in circulating platelets. Blood platelets help initiate clotting and block small holes in the vessel walls. If the platelet count drops, the heparin has to be discontinued and some other medicine considered. Heparin can also create bruises and welts at the injection site. The injections can get infected if not done sterilely.

The side effects of prednisone dissuade your doctor from recommending this medication as a long-term first choice. Prednisone also induces bone loss, in addition to weight gain, hypertension, sleep and mood disturbances, glucose intolerance, and aseptic necrosis of the femoral head (hip).

Despite possible risks involved with this therapy, the benefits can help a couple conceive and give birth to a healthy child. Knowing these benefits vs. risks, you must decide if the tradeoffs are worth the risk and if this therapy is something that you would pursue.

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