Lupron
Lupron, a GnRH agonist, and Antagon, a GnRH antagonist, are injectable medications used to down-regulate or block the release of certain hormones, such as luteinizing
hormone (LH) and follicle stimulating hormone (FSH), from the pituitary. Without LH
or FSH, the ovary will not produce follicles which, in turn, will
decrease the production of estrogen and progesterone. When Lupron
is discontinued, the pituitary gland will resume normal production
of FSH and LH.
In
fertility treatment, Lupron or Antagon are primarily used during superovulation
cycles to control the release of the hormones described above.
Daily exposure to Lupron or Antagon reduces the chance that LH will be released prematurely causing rupture of the ovarian follicles.Without these medication up to 30% of superovulation cycles can experience spontaneous
premature release of LH leading to cancellation of the cycle.
With Lupron or Antagon control, this figure is reduced to less than 10%.
Lupron
can also be used to cause medical menopause for the treatment
of endometriosis, breast cancer, prostate cancer, and uterine
fibroids. Lowered estrogen levels tend to curb the progression
of the disease and its associated pain. In the case of endometriosis,
the pain free interval may be extended, avoiding the need for additional
surgery. Prolonged
usage of Lupron, however, will accelerate bone
loss (osteoporosis) and increase the risk of coronary artery disease.
After Lupron use, an increased
number of ovarian follicles may be produced leading to a higher risk of multiple
gestation, i.e., twins, triplets..
Pergonal/Follistim/Clomiphene
Citrate
Pergonal,
Follistim, and Clomiphene Citrate are medications indicated for
women who are infertile. The purpose of these drugs is to induce
or enhance ovulation, or, to super-stimulate the ovaries of women
undergoing assisted reproductive technologies such as IVF/GIFT/ZIFT.
Pergonal consists of 75 IU of FSH (follicle stimulating hormone)
and 75 IU of LH (luteinizing hormone) per ampule and is given
by injection. Follistim consists of 75 IU of recombinant FSH per ampule
and is also given by injection. There are other injectable forms of these hormones, such as Repronex or Gonal F, that are also used for ovarian stimulation, however, we tend to use either Pergonal alone or in combination with Follistim. As a group, these injectable meds are called gonadotropins.
Clomiphene is an anti-estrogen pill that causes the pituitary gland to secret greater amounts of FSH thus stimulating the ovary to produce more than one follicle per cycle.
The
potential risks of these drugs include:
- Ovarian
hyperstimulation syndrome. Some women may develop significant
enlargement of the ovaries that may, in severe cases, require
hospitalization, intravenous fluid replacement, plasma expanders,
and removal of the abdominal fluid.
- Multiple
births
a)
15% of all pregnancies are twins.
b) 5% are triplets or greater.
- The
potential for selective reduction of multiple gestations
to enhance fetal viability and maturity.
- Higher
miscarriage rate.
- Higher
risk of pre-term/premature delivery.
a)
An arterial thrombosis (blood clot) can occur with severe
ovarian hyperstimulation syndrome.
b)
A venous thrombosis (blood clot) can occur unpredictably,
but is associated most commonly with persons who have a personal
or family history of venous thrombosis or clotting disorder.
- Hemoperitoneum (blood in the abdominal space) can occur from ruptured ovarian cysts.
- Febrile reaction/cellulitis may occur at the injection site.
- Ovarian cancer. One study suggests that the use of Clomiphene increases the lifetime risk of developing ovarian cancer by 4.5%. Reliable data is not available for injectable gonadotropins (Pergonal), but the risk may be slightly higher.
- Adnexal Torsion (twisting of the ovary) occurs in less than 1% of the cases. This occurs when the stimulated ovary twists on itself and cuts off its own blood supply; surgery is required to untwist or remove the affected ovary.
- Ectopic/Tubal Pregnancy. The incidence is increased slightly from 1-2% to 1-3%.
The usual dosage of Pergonal or Follistim varies from 1-6 ampules
per day for 7-14 days. The usual dosage of clomiphene citrate
is 50-250 mg per day for 5 days. The dosage of these medications is carefully monitored by the use of ultrasound to evaluate the response of the ovary and production of follicles.
Human
Chorionic Gonadotropin (hCG)
Human
Chorionic Gonadotropin (hCG) is the hormone produced by the human
placenta. It is also used to trigger ovulation in women treated
with Pergonal, Follistim, or clomiphene citrate. The action of
hCG is similar to that of LH in that it stimulates the eggs/oocytes
to mature and be released from the ovary.
HCG
can cause headaches, irritability, depression; or swelling and
pain at site of injection. When used with Pergonal or Follistim,
it may cause or increase ovarian hyperstimulation syndrome.
The
usual dosage of hCG is 5,000-10,000 units given by injection at
the exact time the physician or nurse practitioner advises.
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 used 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 encountered
during superovulation therapy. 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. Current information suggests
that progesterone supplementation does not increase the risk of
birth defects over the baseline rate of approximately 3%.
Progesterone
supplementation may be administered orally, intramuscularly, or
vaginally. Side effects include: lethargy, mood swings, depression, and
breast tenderness; local pain or irritation at the site of the
injection, and irritation of the vagina or perineum (with vaginal
medication).
The
usual dosage for Progesterone given by injection is 50-100mg once
a day. The usual dosage for Progesterone given by vaginal tablets
is 50-200mg three to four times per day. The usual dosage for oral preparations is 100-200 mg. two to three times per day.
Estrogen
The
use of supplemental estrogen in pregnancy is a controversial subject.
Diethylstilbestrol (DES), a semi-synthetic estrogen, was given
during the 1940's through the 1960's prevent miscarriages in high-risk
women. It was later discovered that this drug caused certain abnormalities
of the cervix and led to a higher incidence of vaginal cancer
in the female offspring and testicular cancer in the male offspring who were
exposed to the drug. A current review of the literature supports
the safety of supplemental estrogen during pregnancy.
The estrogen used today, closely resembles the estrogen
produced by the ovary. The most active form is that estrogen is estradiol,
typically in the form of 17-beta estradiol. Currently this medication
is available in an oral (Estrace), injectable (Estradiol valerate),
vaginal (Estrace Cream) and transdermal (Estraderm) preparations.
These hormones differ from DES in that they are biologically identical
to estrogen made by the ovary.
During the 1970's and 1980's, Russia and Slavic countries used
these estrogen preparations as therapy for patients suffering
from recurrent miscarriage. This treatment achieved moderate success with
no reported increase in fetal anomalies. In the western countries,
the explosion of assisted reproductive technologies, e.g., IVF,
has created a need to re-implant frozen embryos into hormone manipulated
uterus. Since the corpus luteum is not functioning in the uterus of
the woman undergoing this procedure, she will require supplemental
hormones until she has passed through the first 8 weeks of the pregnancy.
There have been no reported increases in the rate of fetal anomalies
in infants born using this thraetment plan, however, recent reports of increased
incidence of congenital anomalies have been associated with fresh
ART/IVF cycles. In a woman who was born without ovaries and who
received donated embryos, there was no increase in fetal anomalies
using the hormonal supplementation needed to support the pregnancy.
The largest group of women achieving pregnancy with the use of
supplemental estrogen is the group who utilized super-ovulation
in association with IVF, GIFT, or ZIFT. During a cycle that is
stimulated to produce multiple follicles, natural estrogen (estradiol)
levels are 3-10 times higher than a normal cycle. Exposure to
such high levels of estrogen has not been associated with an increase
in the rate of fetal anomalies. French researchers have also published
higher implantation and pregnancy rates with the use of supplemental
estrogen before ovulation and in the luteal phase that occurs
after ovulation.
At IVF Phoenix we may recommend the use of estrogen in the follicular
phase of development (before ovulation) along with additional estrogen
starting 4-5 days after the LH surge or "trigger shot" of hCG.
In a normal spontaneous cycle, estrogen drops following the LH
surge and slowly increase during the luteal phase. With ART cycles,
we attempt to imitate this process and improve the development
of the lining of the uterus through the use of vaginal, transdermal,
or injectable estrogen. (The bioavailability--amount the body
can use--is greater when the medication is given by one of these
routes rather than when it is taken orally.)
Experience has shown that there is a significant difference in
estrogen levels in women who experience recurrent spontaneous
miscarriages. It is not clear if factors leading to miscarriage
also caused a reduction on the production of estrogen, or, if low
estrogen somehow played a role in causing the miscarriage. What
is clearer is the fact that newer estrogen products are structurally
and biologically similar to estrogen produced by the ovary and
placenta and exposure to elevated levels of estrogen does not
create an increase in fetal malformations.
Aspirin/Heparin/Prednisone
The
use of heparin, baby aspirin, and prednisone may be suggested
to help you achieve or maintain a pregnancy. Currently, there is little evidence to support the use of these medicines during pregnancy except in cases of recurrent pregnancy loss or pregnancy complicated by preeclampsia; however, the benefit of heparin, aspirin and prednisone to acheive pregnancy has been extrapolated from work that was done on women with recurrent pregnancy loss.Treatment of women with unexplained infertility is based on the premise that these women may, in fact, be achieving fertilization
and embryo development but the embryo fails to implant. In a real sense, early miscarriage may be occurring. There are many
theories related to the implantation failure: lack of blocking antibodies, the
presence of autoimmune disorders that activate the immune system
to over-respond and injure the pregnancy; the prevalence of silent
clotting abnormalities. It is our belief that endometriosis,
salpingitis isthmica nodosa, Hashimoto's thyroiditis, Raynaud's
disease, lupus, rheumatoid arthritis, and other autoimmune disorders
may initiate a response that creates a hypercoagulable (hyperactive clotting) state when pregnancy occurs.
Blood flow to the ovary and endometrium(uterine lining) is predictive of pregnancy outcome in women who are infertile. It has been demonstrated that low dose aspirin taken prior to conception improves uterine lining and, hence, pregnancy outcome. Dr. Alan Beer, Chicago, published improved pregnancy rates in women who experienced pregnancy loss when those women were given heparin from cycle day three onwards. The use of heparin and aspirin in women with infertility has also been published.
Infertility is associated with greater perinatal morbidity and mortality: there is a three-fold risk of stillbirth, five-fold risk of preeclampsia, four-fold risk of miscarriage, two-fold risk of pre-term labor, and an increased risk of intrauterine growth retardation. Review of the literature shows an increasing interest in the possible association of these pregnancy complications and increased clotting and fibrin formation. It is my belief that the invariance among these factors may be the deposition of fibrin (what our bodies generate and what creates a scab), along with spasm of blood vessels, that leads to abnormalities of placentation. What this means is that there may be a hidden clotting disorder(s) that is unmasked during pregnancy which causes interference with the maternal-fetal interface. This theory is reinforced by the fact that excessive fibrin deposition is the most common finding of the placentas in these pregnancy complications. When women with elevated soluble fibrin monomer (greater than 40) were identified and treated in our practice, a total of 8 women, 6 achieved pregnancy and 4 of the 6 delivered babies at 30-34 weeks gestation. Those same women, left untreated, would have had a 5% risk of stillbirth.
Current literature demonstrates a direct connection between polycystic ovarian syndrome, insulin resistance, and increased blood clotting. This relationship is due to a deficiency in the anti-clotting mechanism that creates a problem with the normal clotting process. The end result is an increase in the deposition of fibrin. It is my belief that elevated fibrin deposition is associated with many abnormal reproductive conditions, including infertility and pregnancy loss.
During the past several years, much interest has been focused on the role of nitric oxide (NO) as an enhancer of uterine blood flow and a mediator of dilation of the smooth muscle like that which makes up blood vessels. The use of heparin, a naturally occurring substance produced by our blood vessels, increases nitric oxide and helps maintain blood flow which in turn leads to improved blood flow throughout the body. As a result, hands are warmer, skin is less blotchy, and most women with thin endometrial linings improve. (Viagra, L-arginine, and calcium channel blockers also increase nitric oxide.) Because a significant number of women in our practice have defined clotting problems, heparin is utilized to address both issues of blood clotting and spasms of the blood vessels. In addition, heparin can be used safely during pregnancy because it is a large molecule that does not pass through the placenta. Given twice a day by injection into the fat (subcutaneously), the dosage is monitored by a blood test (activated partial thrombin time, or, PTT) drawn six hours after the morning dose. Dosages are titrated to maintain a PTT slightly above normal since excessive amounts of heparin will prevent the blood from clotting and can potentially cause a problem with bleeding. Short-term use of heparin is considered safe; risks are similar to those experience by people who receive it as protection against blood clots following surgery. Thrombocytopenia, a drop in platelets, occurs in 1-3% of the patients on long-term heparin therapy and most often resolves spontaneously once the heparin has been discontinued. Because platelets help initiate the blood clotting mechanism that blocks small holes in the vessel walls, if thrombocytopenia occurs, heparin will have to be discontinued and another medication used in its place. Heparin can also cause bruises or wheals to form at the site of the injection and infection can occur if the injections are not done using aseptic technique.
Aspirin is used in conjunction with the heparin to treat “sticky” activated platelets. “Sticky” platelets may be due to spasms in small blood vessels which causes a shearing affect on them. The use of aspirin is thought to decrease the stickiness of platelets, thereby allowing them to flow through the small vessels more easily. Chronic use of aspirin, however, may cause stomach irritation, intestinal bleeding, or ringing in the ears (tinnitus). If any of these symptoms occur, your doctor will either monitor the symptoms or have you discontinue the medication. Because aspirin can pass through the placenta, it can affect the ductus arteriosus in the fetus and cause it to narrow. This, in turn, can lead to potential closure causing an alteration in fetal blood flow and decreased oxygen levels in the fetus. This narrowing effect is not noted until after 20 weeks gestation and if it occurs, you can expect to discontinue the medication. In most cases, the narrowing should stop and may, in fact, reverse. For this reason (and perhaps others), timing for discontinuing aspirin and heparin remains controversial and will vary from doctor to doctor. Regardless of the duration of treatment, it is important to know that the use of these medications has been shown to be safe up to two days before delivery.
Prednisone is used when there is evidence of autoimmune disorders. These conditions include the presence of antinuclear antibodies (ANA), antiphospholipid antibodies (APA), or antithyroid antibodies (ATA), etc. Review of the literature reveals many articles that support the association of a positive ANA with poor pregnancy outcome, so, for this reason, we add prednisone to protect pregnancy from injury due to an autoimmune response. Long-term use of steroids can lead to weight gain, bone loss, hypertension, sleep and mood disturbances, glucose intolerance, and aseptic necrosis of the femoral head, so treatment is monitored to keep exposure to a minimum.
Since an embryo in early implantation does not require the larger blood flow required for a 6 weeks gestation, why would hypercoagulation be a problem during that stage of development? Thisis an excellent question and one that we continually struggle to answer. Obviously, hypercoagulation is not the only issue in the early implantation; autoantibodies may be also be a problem. In an older study of In-Vitro Fertilization (IVF) patients, the presence of APA significantly reduced the pregnancy outcome by one half. In a small prospective trial, women were treated with a steroid during the follicular development and luteal phases of IVF and GIFT cycles. Those women who did not have a positive APA received no benefit or change in pregnancy rates whether or not they used steroids. In women whose positive APA was treated with steroids, 8 of 10 got pregnant; women who had a positive ANA but declined steroid treatment, none of the 25 studied conceived. Our observation in the laboratory is that embryos from certain individuals display fragmentation; the greater the amount of fragmentation that is present, the less likely the embryo will result in a pregnancy. This fragmentation, we believe, is immunologically-related giving further support to the use of steroids when indicated.
