Ask Our Doctors – Archive
Our Medical Directors are outstanding physicians that you will find to be very personable and compassionate, who take care to ensure that you have the most cutting-edge fertility treatments at your disposal. This is your outlet to ask your questions to the doctors.
Does your clinic have the option of purchasing donor sperm?
Do you offer the IUI option? If so, what is the average cost?
We refer our patients tom a registered sperm bank for donor sperm. And yes! We do offer IUI.
Intrauterine insemination (IUI), the injection of sperm into the uterus by means of a catheter directed through the cervix, has been practiced for many years. The premise of this procedure is that sperm can reach and fertilize the egg more easily if placed directly into the uterine cavity.
In the early ‘60s, physicians were injecting small quantities of raw, untreated semen (sperm plus the seminal plasma) directly into the uterus at the time of expected ovulation. However, when more than 0.2 ml of semen was injected into the uterus, serious and sometimes life endangering shock-like reactions often occurred. It was subsequently identified that the reason for such reactions related to the presence of prostaglandins within the seminal plasma. This led to the practice of injecting small amounts (less than 0.2 ml) of raw semen. However, the pregnancy rates were dismal and side effects, such as severe cramping and infection were rampant.
Soon after establishing the Northern Nevada Fertility Center in Reno in 1982, the nation’s first private IVF program, Dr. Sher began to recognize the potential advantage of washing and centrifuging raw semen to separate sperm from the seminal fluid, and thereby remove prostaglandins that cause most of the problems. He subsequently introduced and, thereupon, became the first to publish, on IUI in the prestigious journal, Fertility and Sterility (April 1984).
INDICATIONS FOR IUI
Artificial insemination with cryopreserved donor (non-partner) sperm:
The recognition of HIV infection as a sexually transmitted disease, coupled with the fact that the virus is present in semen months before it can be detected in the blood, mandates that all donors have their semen cryopreserved (frozen) and stored for at least six months, whereupon they will be re-tested for HIV infection. Only upon confirmation of a negative test should the cryopreserved semen specimen be thawed and used for insemination. Since cryopreservation inevitably reduces sperm motility and function, it is not adequate to simply thaw the frozen specimen and then inseminate the raw semen into the vagina. Rather, the semen specimen should be processed for IUI. Provided that the recipient is ovulating normally, there is no specific need to administer fertility drugs.
Artificial insemination with husband’s sperm:
In cases of sexual dysfunction (impotence, retrograde ejaculation, etc.) or timing issues, a husband’s sperm may need to be collected and processed in preparation for IUI.
Cervical mucus insufficiency:
Sometimes the cervical mucus acts as a barrier to the activation and passage of sperm as it passes through the cervical canal. Such hostility may be due to poor physical qualities of the mucus, cervical infection, or the presence of anti-sperm antibodies. In all but the latter case, IUI can readily be performed during natural cycles, unless the woman has ovulation dysfunction. However, when infertility results from the presence of antibodies in the cervical mucus, IUI will be ineffectual and should be replaced by IVF.
Abnormal Ovulation:
In some cases where the woman requires the use of fertility drugs to induce normal ovulation, the concomitant performance of IUI can optimize pregnancy rates.
SELECTING THE OPTIMAL CONTROLLED OVARIAN STIMULATION (COS) PROTOCOL FOR IUI
ORAL FERTILITY DRUGS:
Oral fertility drugs such as clomiphene and letrozole are gentle ovarian stimulants that are in general best used in younger women who have normal egg reserve but who suffer from either ovulatory dysfunction, mild sperm issues, or unexplained infertility. In cases of unexplained infertility, the American Society for Reproductive Medicine (ASRM) recommends starting with 3-4 cycles of ovarian stimulation and intrauterine insemination (IUI) with clomiphene or letrozole. Clomiphene or letrozole alone, timed intercourse alone, or IUI alone do not significantly increase the per monthly chance of conceiving with unexplained infertility. It is the combination of these oral stimulants plus IUI that can start to increase the pregnancy rate.
Clomiphene is by far the most widely prescribed agent for the induction of human ovulation for women who do not ovulate, those with dysfunctional ovulation and women with “unexplained” infertility. When used in young women (who have adequate ovarian reserve) with these problems the viable pregnancy rate is reported as being between 6% and 10% per cycle of treatment. Aside from conventional ovulation induction, clomiphene has been used in preparing women for intrauterine insemination and even for IVF.
The main reasons for clomiphene’s popularity is its low cost, simplicity of use, and the low risk of dangerous complications such as severe ovarian hyperstimulation syndrome (OHSS).Clomiphene treatment can be initiated at a dose of 50 mg (orally) daily for 5 days but it can be increased to as much as 200mg per day, starting on cycle day 2, 3, 4, or 5. A spontaneous LH surge will usually follow within about 8-9 days of the last 50mg dosage. In some cases, 10,000U of hCG can be given as a trigger when there is at least one ovarian follicle of 18-20 mm in size.
Clomiphene works by inducing ovulation through its “antiestrogen effect” which, by blocking estrogen receptors in an area of the brain known as the hypothalamus, tricks the brain into “thinking” that estrogen levels are low. In response, the hypothalamus prompts the pituitary gland to release an exaggerated amount of follicle-stimulating hormone (FSH), which in turn stimulates the growth and development of ovarian follicles, ultimately resulting in a surge in the release of pituitary LH. About 38-42 hours later, ovulation occurs from one or more of the larger follicles. As the follicles grow, they release more and more estrogen into the bloodstream, thus closing the feedback circle that the hypothalamus initiated in response to the anti-estrogen properties of Clomiphene.
Letrozole is an oral non-steroidal aromatase inhibitor that has been used (off-label) for ovulation induction as part of the IVF process since 2001.When Letrozole blocks aromatase activity, there is a drop in E2 levels and a concomitant increase in FSH (and LH) secretion that stimulates growth of ovarian follicles and with it, estrogen production/release. Unlike clomiphene, Letrozole is not an anti-estrogen at the cellular level and therefore does not cause the cervical mucus to dry up or the endometrium to become less responsive to estrogen (and hence thinner). However, like clomiphene, Letrozole can cause an increase in pituitary LH production/release that can cause increased ovarian androgen (testosterone) production. As previously stated, while small amounts of testosterone are required to promote estradiol production with follicle growth and egg development, an excessive amount of ovarian testosterone inhibits egg and follicle development, thereby increasing the potential for egg aneuploidy (“incompetence). It therefore may be unwise to use letrozole or clomid in IVF cycles, especially in older women and those with DOR who in general tend to have increased LH biological activity. Letrozole can be used in patients with absent or dysfunctional ovulation that is NOT related to DOR. It can also be used as an alternative to clomiphene citrate which, because of its ant-estrogenic effect, sometimes causes poor endometrial linings.
The usual starting dose of Letrozole is 2.5 mg orally daily for 5 days starting on day 2, 3, 4 or 5 of the menstrual cycle. The daily dosage can be increased to 5 or 7.5 mg if required. Interestingly, some well-done studies suggest that letrozole is a more effective means of treating infertility than clomiphene for women with polycystic ovary syndrome, with evidence of higher rates of ovulation and rates of major congenital anomalies that were not significantly different.
Side effects for both clomid and letrozole are uncommon but similar and include hot flashes, sweating, nausea, tiredness, diarrhea, and joint pain.
There are several factors that need to be considered carefully before deciding to prescribe clomiphene to any woman:
?Clomiphene citrate therapy is less effective than gonadotropin therapy and its efficacy declines with advancing age. Ideally the use of clomiphene should in our opinion be restricted to younger women (under 35 years) who have normal “ovarian reserve” (as assessed by basal blood FSH, and anti-Mullerian hormone (AMH) levels). These are the women who are most likely to respond by producing multiple follicles. It is desirable that at least 2 sizeable follicles (>15mm) develop on clomiphene treatment, to override the “anti-estrogenic” effects of this drug and so insure adequate cervical mucus production as well as the development of a receptive endometrium.
?Clomiphene should usually not be administered for more than 3 consecutive (back-to- back) cycles: If used back-to-back for more than 3 consecutive cycles, clomiphene is not only ineffective, but starts to function as a “relative” contraceptive! This is often a shocking revelation to many women. Clomiphene’s anti-estrogenic effect is not confined to the hypothalamus. Any cells that have a high concentration of estrogen receptors will also be so affected. The cervical glands (that produce estrogenic mucus to facilitate sperm transport and the endometrial lining (endometrium) that thickens under the effect of estrogen are also highly vulnerable to a buildup of antiestrogen effects over successive back-to back cycles of clomiphene therapy. Therefore, with >3 consecutive back-to back clomiphene cycles cervical mucus tends to thicken and dry up and the endometrium will thin, seriously reducing the likelihood of success. These anti-estrogenic manifestations require that following 3 back-to back clomiphene cycles of stimulation there be at least one resting (non-clomiphene treated) cycle, before doing a 4th cycle.
?Clomiphene should not be used in older women or in women who have diminished ovarian reserve (DOR): With clomiphene stimulation, the release of pituitary FSH is always accompanied by the concomitant release of Luteinizing Hormone (LH). LH causes the ovary to produce male hormone (androgens) and testosterone. The production by the ovaries of a modest amount of testosterone would not present a problem. However, an excessive production of ovarian testosterone prejudices egg development and thus ultimately compromises embryo competency. Older women and women with DOR are the most vulnerable because they tend to have overgrowth (hyperplasia)of ovarian connective tissue (stroma/theca) which is the site where androgens are produced. “Trapped” ovulation (LUF-Syndrome): About 20% of clomiphene cycles are associated with “trapped” ovulation (Luteinized Unruptured Follicle or LUF Syndrome). This means that despite hormone changes suggesting that ovulation has occurred, the egg remains trapped in the follicle. Obviously, this is not conducive to the establishment of a successful pregnancy.
?Women with long gaps between menstruation are often not ideal candidates for clomiphene: Women who consistently have >45 days between their periods will not respond well to clomiphene induction of ovulation and are likely better off going directly to injectable gonadotropins.
?Multiple pregnancy: The incidence of multiple pregnancies with clomiphene induction of ovulation is about 5-10%. This is much lower than the 25% rate encountered when gonadotropins are given to women with absent or dysfunctional ovulation.
Clomiphene therapy is often used as a first line approach to inducing ovulation in women with irregular or absent ovulation such as in women with polycystic ovarian syndrome (PCOS). Its use in our opinion is best confined to women who menstruate/ovulate irregularly (but who bleed at least every 45 days), younger women, women who do not have tubal disease or endometriosis, women under 40 years of age (preferably <35Y), and women who do not have DOR. It should also be avoided when there is co-existing moderate to severe male factor infertility. If pregnancy fails to occur after 3 consecutive cycles of clomiphene therapy, then, it is probably time to consider IVF.
Women with absent or abnormal ovulation that require fertility drugs in preparation for IUI should consider gonadotropins (Menopur, Gonal F, Follistim). Granted, these agents are expensive, but they have no antiestrogenic properties and, in the hands of the experienced physician, their pregnancy rates are 30% greater than with the oral agents.
IUI SUCCESS RATES
Success rates with IUI are contingent upon the following: (1) procedure is being performed for the correct indications, (2) avoiding the performance of IUI when contraindications exist (see below), (3) whether the woman is ovulating normally and (4) the age of the woman. Birth rates per cycle of IUI performed for the correct indications are reported to be about 15% for women under 30 years of age, 12% for women 30-35 years, 7-8% for women 35-39 years, and less than <3% for women over 40 years.
RELATIVE CONTRAINDICATIONS TO INTRAUTERINE INSEMINATION
•Age: Women over the age of 40 years have less than a 3% chance of conceiving through IUI .
•Tubal disease: Women with evidence of bilaterally blocked fallopian tubes by virtue of hysterosalpingogram x-ray require IVF. Since infection and inflammation damage the intricate inner lining of the fallopian tubes, there is no surgery to the outside of the tube(s) that will remedy damage done to the inner lining. Women with one patent or open fallopian tubes can try an IUI approach, but it is often the case that the same insulting factor that has closed one tube has partially damaged the other, and this may lower success. Moreover, the incidence of ectopic pregnancy is about 1 in 6. Bypassing the “damaged plumbing” with IVF is the only rational treatment in such cases.
• Male Factor Infertility: The performance of IUI in cases of severely abnormal semen parameters (< 10 million total moving sperm per IUI) does not significantly improve success rates over regular and well-timed intercourse alone. IVF with intracytoplasmic sperm injection (IVF/ICSI) is the best if not the only method to address severe male infertility. •Endometriosis: While the exact cause of endometriosis remains an enigma, it is now apparent that immunologic dysfunction is a feature of this disease, and that a toxic environment exists in the pelvis (surrounding the tubes and ovaries) in patients with this condition. Consequently, ovulation, whether spontaneous or induced by fertility drugs, commits the egg to pass through a toxic pelvic environment to reach the sperm waiting in the fallopian tube. This significantly reduces the egg’s fertilization potential. Furthermore, once the fertilized egg reaches the uterus, immunologic factors associated with endometriosis increase the risk of the embryo being rejected before pregnancy can be diagnosed. Such women may experience repeated “mini-miscarriages.” Despite these anti-fertility influences, many women with mild endometriosis do conceive on their own or following ovarian stimulation with fertility drugs. However, for reasons already referred to, the chances of conception are significantly reduced, and if they are ovulating normally on their own, the addition of fertility drugs will afford no additional benefit. Simply put, women in their late 20’s to early 30’s, who have the time to wait, can anticipate about a 40% chance of conceiving on their own within two or three years, contingent upon their ovulating normally and having fertile male partners. The occurrence of pregnancy in the latter cases occurs despite, rather than due to, such treatment. Unless their quality of life is lowered by painful symptoms, women with endometriosis could therefore consider deferring invasive treatments in favor of a “wait-and-see” approach. Conversely, for women over the age of thirty-five whose egg quality is inevitably on the decline, IVF offers the rational approach. IUI’s RISK FOR MULTIPLE BIRTHS Normally ovulating women usually develop several follicles (cysts containing oocytes and the cells that nurture them) and produce estrogen during the menstrual cycle. All but one (and sometimes two) of the follicles fail to develop to the point of ovulation. The process is known as “selection”. In all normally ovulating women, the one or two follicles selected to ovulate will inevitably be larger than the remaining follicles. Simply put, one or two follicles will always show enhanced development over the others, and as soon as these selected follicles ovulate, all the remaining follicles are rendered incapable of following suit. As a result, normally ovulating women do not have a significantly greater incidence of high order multiple pregnancies. In contrast, women who do not ovulate at all, and those who ovulate dysfunctionally, following the administration of fertility drugs for ovarian stimulation, may have numerous follicles develop at the same rate and several eggs can be ovulated simultaneously. This translates into a greater chance of pregnancy, but also into a greater chance of multiple pregnancies. It is interesting that almost all reported cases of high order multiple pregnancies (greater than twins) following the use of fertility drugs have occurred in women who do not ovulate normally on their own. It follows that only those women with absent or dysfunctional ovulation are at risk for high order multiple pregnancies. They, therefore, need to be counseled regarding the consequences of premature birth and the availability of selective pregnancy reduction towards the end of the third month of pregnancy. Another alternative is to avoid the issue completely by choosing IVF, where the number of embryos transferred to the uterus can limit the number of potential babies. Intrauterine insemination (IUI), like any other form of fertility treatment, can be of great value if used appropriately and selectively for the correct indication. The use of fertility drugs should not be regarded as a necessary adjunct in all cases of IUI, which in turn should not be considered as a required preliminary to IVF. Geoff Sher 702-533-2691
1st Draw – June 27th – 87 (12 DPO)
2nd Draw – June 29th – 169 (14 dpo). i am a 33y female with 5 chem in the last year. Very nervous. Please share your throughts
I assume these are your blood hCG levels.Accordingly, thus far the rise in blood level is consistent with normality!
Good luck!
Geoff Sher
Hi Dr. – I am 34 years old. I have three healthy children, and three second trimester miscarriages (13 weeks, 14 weeks, and 19 weeks) The 13 week loss was between my 2nd and third children and the last two were in a row. I get pregnant easily, and have had no other pregnancy complications. Every single part of my work up from genetics, to the babies’ chromosomes, to RPL bloodwork has come back normal – with the exception of MTHFR which has mostly been dismissed. I took 2 baby aspirin a day the last pregnancy to no avail. Is there any hope I can have another baby? The only other thing that has been suggested is Lovenox, but is there anything else to try?
You have experienced 2nd trimester recurrent pregnancy loss. The first thing to rule out is cervical incompetence. Then, congenital abnormality of the uterus, uterine lesions (e.g. fibroids) etc can also do this. An overall view of recurrent pregnancy loss is in my opinion as below:
When it comes to reproduction, humans are the poorest performers of all mammals. In fact we are so inefficient that up to 75% of fertilized eggs do not produce live births, and up to 30% of pregnancies end up being lost within 10 weeks of conception (in the first trimester). RPL is defined as two (2) or more failed pregnancies. Less than 5% of women will experience two (2) consecutive miscarriages, and only 1% experience three or more.
Pregnancy loss can be classified by the stage of pregnancy when the loss occurs:
•Early pregnancy loss (first trimester)
•Late pregnancy loss (after the first trimester)
•Occult “hidden” and not clinically recognized, (chemical) pregnancy loss (occurs prior to ultrasound confirmation of pregnancy)
•Early pregnancy losses usually occur sporadically (are not repetitive).
In more than 70% of cases the loss is due to embryo aneuploidy (where there are more or less than the normal quota of 46 chromosomes). Conversely, repeated losses (RPL), with isolated exceptions where the cause is structural (e.g., unbalanced translocations), are seldom attributable to numerical chromosomal abnormalities (aneuploidy). In fact, the vast majority of cases of RPL are attributable to non-chromosomal causes such as anatomical uterine abnormalities or Immunologic Implantation Dysfunction (IID).
Since most sporadic early pregnancy losses are induced by chromosomal factors and thus are non-repetitive, having had a single miscarriage the likelihood of a second one occurring is no greater than average. However, once having had two losses the chance of a third one occurring is double (35-40%) and after having had three losses the chance of a fourth miscarriage increases to about 60%. The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to a non-chromosomal (repetitive) cause such as IID. It follows that if numerical chromosomal analysis (karyotyping) of embryonic/fetal products derived from a miscarriage tests karyotypically normal, then by a process of elimination, there would be a strong likelihood of a miscarriage repeating in subsequent pregnancies and one would not have to wait for the disaster to recur before taking action. This is precisely why we strongly advocate that all miscarriage specimens be karyotyped.
There is however one caveat to be taken into consideration. That is that the laboratory performing the karyotyping might unwittingly be testing the mother’s cells rather than that of the conceptus. That is why it is not possible to confidently exclude aneuploidy in cases where karyotyping of products suggests a “chromosomally normal” (euploid) female.
Late pregnancy losses (occurring after completion of the 1st trimester/12th week) occur far less frequently (1%) than early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix rendering it able to act as an effective valve that retains the pregnancy (i.e., cervical incompetence) is in fact one of the commonest causes of late pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum) and uterine fibroid tumors. In some cases intrauterine growth retardation, premature separation of the placenta (placental abruption), premature rupture of the membranes and premature labor can also causes of late pregnancy loss.
Much progress has been made in understanding the mechanisms involved in RPL. There are two broad categories:
1.Problems involving the uterine environment in which a normal embryo is prohibited from properly implanting and developing. Possible causes include:
•Inadequate thickening of the uterine lining
•Irregularity in the contour of the uterine cavity (polyps, fibroid tumors in the uterine wall, intra-uterine scarring and adenomyosis)
•Hormonal imbalances (progesterone deficiency or luteal phase defects). This most commonly results in occult RPL.
•Deficient blood flow to the uterine lining (thin uterine lining).
•Immunologic implantation dysfunction (IID). A major cause of RPL. Plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implant.
•Interference of blood supply to the developing conceptus can occur due to a hereditary clotting disorder known as Thrombophilia.
2.Genetic and/or structural chromosomal abnormality of the embryo.Genetic abnormalities are rare causes of RPL. Structural chromosomal abnormalities are slightly more common but are also occur infrequently (1%). These are referred to as unbalanced translocation and they result from part of one chromosome detaching and then fusing with another chromosome. Additionally, a number of studies suggest the existence of paternal (sperm derived) effect on human embryo quality and pregnancy outcome that are not reflected as a chromosomal abnormality. Damaged sperm DNA can have a negative impact on fetal development and present clinically as occult or early clinical miscarriage. The Sperm Chromatin Structure Assay (SCSA) which measures the same endpoints are newer and possibly improved methods for evaluating.
IMMUNOLOGIC IMPLANTATION DYSFUNCTION
Autoimmune IID: Here an immunologic reaction is produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are APA and antithyroid antibodies (ATA).
But it is only when specialized immune cells in the uterine lining, known as cytotoxic lymphocytes (CTL) and natural killer (NK) cells, become activated and start to release an excessive/disproportionate amount of TH-1 cytokines that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such activation requires highly specialized blood test for cytokine activity that can only be performed by a handful of reproductive immunology reference laboratories in the United States.
Alloimmune IID, i.e., where antibodies are formed against antigens derived from another member of the same species, is believed to be a relatively common immunologic cause of recurrent pregnancy loss.
Autoimmune IID is often genetically transmitted. Thus it should not be surprising to learn that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma or autoimmune hypothyroidism (Hashimoto’s disease), autoimmune hyperthyroidism (Grave’s disease), rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Since autoimmune IID is usually associated with activated NK and T-cells from the outset, it usually results in such very early destruction of the embryo’s root system that the patient does not even recognize that she is pregnant. Accordingly the condition usually presents as “unexplained infertility” or “unexplained IVF failure” rather than as a miscarriage.
Alloimmune IID, on the other hand, usually starts off presenting as unexplained miscarriages (often manifesting as RPL). Over time as NK/T cell activation builds and eventually becomes permanently established the patient often goes from RPL to “infertility” due to failed implantation. RPL is more commonly the consequence of alloimmune rather than autoimmune implantation dysfunction.
However, regardless, of whether miscarriage is due to autoimmune or alloimmune implantation dysfunction the final blow to the pregnancy is the result of activated NK cells and CTL in the uterine lining that damage the developing embryo’s “root system” (trophoblast) so that it can no longer sustain the growing conceptus. This having been said, it is important to note that autoimmune IID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy, and alloimmune IID is not. It is much more difficult to treat successfully, even with the use of immunotherapy. In fact, in some cases the only solution will be to revert to selective immunotherapy plus using donor sperm (provided there is no “match” between the donor’s DQa profile and that of the female recipient) or alternatively to resort to gestational surrogacy.
DIAGNOSING THE CAUSE OF RPL
In the past, women who miscarried were not evaluated thoroughly until they had lost several pregnancies in a row. This was because sporadic miscarriages are most commonly the result of embryo numerical chromosomal irregularities (aneuploidy) and thus not treatable. However, a consecutive series of miscarriages points to a repetitive cause that is non-chromosomal and is potentially remediable. Since RPL is most commonly due to a uterine pathology or immunologic causes that are potentially treatable, it follows that early chromosomal evaluation of products of conception could point to a potentially treatable situation. Thus I strongly recommend that such testing be done in most cases of miscarriage. Doing so will avoid a great deal of unnecessary heartache for many patients.
Establishing the correct diagnosis is the first step toward determining effective treatment for couples with RPL. It results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include:
•Karyotyping (chromosome analysis) both prospective parents
•Assessment of the karyotype of products of conception derived from previous miscarriage specimens
•Ultrasound examination of the uterine cavity after sterile water is injected or sonohysterogram, fluid ultrasound, etc.)
•Hysterosalpingogram (dye X-ray test)
•Hysteroscopic evaluation of the uterine cavity
•Full hormonal evaluation (estrogen, progesterone, adrenal steroid hormones, thyroid hormones, FSH/LH, etc.)
•Immunologic testing to include:
a)Antiphospholipid antibody (APA) panel
b)Antinuclear antibody (ANA) panel
c)Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies)
d)Reproductive immunophenotype
e)Natural killer cell activity (NKa) assay (i.e., K562 target cell test)
f)Alloimmune testing of both the male and female partners
TREATMENT OF RPL
Treatment for Anatomic Abnormalities of the Uterus: This involves restoration through removal of local lesions such as fibroids, scar tissue, and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated.
Treatment of Thin Uterine Lining: A thin uterine lining has been shown to correlate with compromised pregnancy outcome. Often this will be associated with reduced blood flow to the endometrium. Such decreased blood flow to the uterus can be improved through treatment with sildenafil and possibly aspirin.
Sildenafil (Viagra) Therapy. Viagra has been used successfully to increase uterine blood flow. However, to be effective it must be administered starting as soon as the period stops up until the day of ovulation and it must be administered vaginally (not orally). Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in 42% of women who responded to the Viagra. It should be remembered that most of these women had previously experienced repeated IVF failures.
Use of Aspirin: This is an anti-prostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81 mg orally, daily from the beginning of the cycle until ovulation.
Treating Immunologic Implantation Dysfunction with Selective Immunotherapy: Modalities such as IL/IVIg, heparinoids (Lovenox/Clexane), and corticosteroids (dexamethasone, prednisone, prednisolone) can be used in select cases depending on autoimmune or alloimmune dysfunction.
The Use of IVF in the Treatment of RPL
In the following circumstances, IVF is the preferred option:
1.When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed.
2.In cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.
The reason for IVF being a preferred approach in such cases is that in order to be effective, the immunotherapy needs to be initiated well before spontaneous or induced ovulation. Given the fact that the anticipated birthrate per cycle of COS with or without IUI is at best about 15%, it follows that short of IVF, to have even a reasonable chance of a live birth, most women with immunologic causes of RPL would need to undergo immunotherapy repeatedly, over consecutive cycles. Conversely, with IVF, the chance of a successful outcome in a single cycle of treatment is several times greater and, because of the attenuated and concentrated time period required for treatment, IVF is far safer and thus represents a more practicable alternative
Since embryo aneuploidy is a common cause of miscarriage, the use of preimplantation genetic diagnosis (PGD), with tests such as CGH, can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGD requires IVF to provide access to embryos for testing.
There are a few cases of intractable alloimmune dysfunction due to absolute DQ alpha matching where Gestational Surrogacy or use of donor sperm could represent the only viable recourse, other than abandoning treatment altogether and/or resorting to adoption. Other non-immunologic factors such as an intractably thin uterine lining or severe uterine pathology might also warrant that last resort consideration be given to gestational surrogacy.
The good news is that if a couple with RPL is open to all of the diagnostic and treatment options referred to above, a live birthrate of 70%–80% is ultimately achievable.
GeoffSher
PH: 702-533-2691
I am 36 Y.O. with endometriosis and been through 2 failed IVF cycles now. In both cycles I encountered the same problem (in addition to no pregnancy) I started bleeding within 8 days (1st IVF cycle) and 6 days (2nd IVF cycle) after 5 day embryo transfer despite being on progesterone. In the first cycle I took Duphaston (10 mg) orally 3 times a day. However when I started bleeding early, my doctor switched to Prolutex (25 mg) intramuscular injections (taken in abdomen) once a day. However 2nd cycle I had an even earlier bleed, started spotting on 6th day and despite continuing progesterone started normal to heavy period flow in subsequent days. I have had fresh transfer both cycles and my endometrium lining is quite healthy at 10-11 mm in all cycles. What should be done differently next time?
P.S. I had three failed IUI cycles where I took vaginal progesterone once a day and didn’t bleed until 2-3 days after stopping it.
When women with infertility due to endometriosis seek treatment, they are all too often advised to first try ovarian stimulation (ovulation Induction) with intrauterine insemination (IUI) ………as if to say that this would be just as likely to result in a baby as would in vitro fertilization (IVF). Nothing could be further from reality It is time to set the record straight. And hence this blog!
Bear in mind that the cost of treatment comprises both financial and emotional components and that it is the cost of having a baby rather than cost of a procedure. Then consider the fact that regardless of her age or the severity of the condition, women with infertility due to endometriosis are several fold more likely to have a baby per treatment cycle of IVF than with IUI. It follows that there is a distinct advantage in doing IVF first, rather than as a last resort.
So then, why is it that ovulation induction with or without IUI is routinely offered proposed preferentially to women with mild to moderately severe endometriosis? Could it in part be due to the fact that most practicing doctors do not provide IVF services but are indeed remunerated for ovarian stimulation and IUI services and are thus economically incentivized to offer IUI as a first line approach? Or is because of the often erroneous belief that the use of fertility drugs will in all cases induce the release (ovulation) of multiple eggs at a time and thereby increase the chance of a pregnancy. The truth however is that while normally ovulating women (the majority of women who have mild to moderately severe endometriosis) respond to ovarian stimulation with fertility drugs by forming multiple follicles, they rarely ovulate > 1 (or at most 2) egg at a time. This is because such women usually only develop a single dominant follicle which upon ovulating leaves the others intact. This is the reason why normally ovulating women who undergo ovulation induction usually will not experience improved pregnancy potential, nor will they have a marked increase in multiple pregnancies. Conversely, non-ovulating women (as well as those with dysfunctional ovulation) who undergo ovulation induction, almost always develop multiple large follicles that tend to ovulate in unison. This increases the potential to conceive along with an increased risk multiple pregnancies.
So let me take a stab at explaining why IVF is more successful than IUI or surgical correction in the treatment of endometriosis-related infertility:
1.The toxic pelvic factor: Endometriosis is a condition where the lining of the uterus (the endometrium) grows outside the uterus. While this process begins early in the reproductive life of a woman, with notable exceptions, it only becomes manifest in the 2ndhalf of her reproductive life. After some time, these deposits bleed and when the blood absorbs it leaves a visible pigment that can be identified upon surgical exposure of the pelvis. Such endometriotic deposits invariably produce and release toxins” into the pelvic secretions that coat the surface of the membrane (the peritoneum) that envelops all abdominal and pelvic organs, including the uterus, tubes and ovaries. These toxins are referred to as “the peritoneal factor”. Following ovulation, the egg(s) must pass from the ovary (ies), through these toxic secretions to reach the sperm lying in wait in the outer part the fallopian tube (s) tube(s) where, the sperm lie in waiting. In the process of going from the ovary(ies) to the Fallopian tube(s) these eggs become exposed to the “peritoneal toxins” which alter s the envelopment of the egg (i.e. zona pellucida) making it much less receptive to being fertilized by sperm. As a consequence, if they are chromosomally normal such eggs are rendered much less likely to be successfully fertilized. Since almost all women with endometriosis have this problem, it is not difficult to understand why they are far less likely to conceive following ovulation (whether natural or induced through ovulation induction). This “toxic peritoneal factor impacts on eggs that are ovulated whether spontaneously (as in natural cycles) or following the use of fertility drugs and serves to explain why the chance of pregnancy is so significantly reduced in normally ovulating women with endometriosis.
2.The Immunologic Factor: About one third of women who have endometriosis will also have an immunologic implantation dysfunction (IID) linked to activation of uterine natural killer cells (NKa). This will require selective immunotherapy with Intralipid infusions, and/or heparinoids (e.g. Clexane/Lovenox) that is much more effectively implemented in combination with IVF.
3.Surgical treatment of mild to moderate endometriosis does not usually improve pregnancy potential:. The reason is that endometriosis can be considered to be a “work in progress”. New lesions are constantly developing. So it is that for every endometriotic seen there are usually many non-pigmented deposits that are in the process of evolving but are not yet visible to the naked eye and such evolving (non-visible) lesions can also release the same “toxins that compromise fertilization. Accordingly, even after surgical removal of all visible lesions the invisible ones continue to release “toxins” and retain the ability to compromise natural fertilization. It also explains why surgery to remove endometriotic deposits in women with mild to moderate endometriosis usually will fail to significantly improve pregnancy generating potential. In contrast, IVF, by removing eggs from the ovaries prior to ovulation, fertilizing these outside of the body and then transferring the resulting embryo(s) to the uterus, bypasses the toxic pelvic environment and is therefore is the treatment of choice in cases of endometriosis-related infertility.
I am not suggesting that all women with infertility-related endometriosis should automatically resort to IVF. Quite to the contrary…. In spite of having reduced fertility potential, many women with mild to moderate endometriosis can and do go on to conceive on their own (without treatment). It is just that the chance of this happening is so is much lower than normal.
In young ovulating women (< 35 years of age ) with endometriosis, who have normal reproductive anatomy and have fertile male partners, expectant treatment is often preferable to IUI or IVF. However, for older women, women who (regardless of their age) have any additional factor (e.g. pelvic adhesions, ovarian endometriomas, male infertility, IID or diminished ovarian reserve-DOR) IVF should be the primary treatment of choice. Geoff Sher PH: 702-533-2691
I am 27 years old, recently diagnosed with DOR.
My lab results are:
AFC 0/2
AMH 0.537 ng/mL
Estradiol (day 43) 61 pg/mL
Progesterone (day 43) 0.2 ng/mL
FSH (day 43) 2.8 miu/mL
Total testosterone (day 43) 14 ng/dL
Free testosterone (day 43) 3.1 pg/mL
Prolactin 27.7 ng/mL
DHEA-S 265 mcg/dL
The baseline tests were performed on day 43 due to me having irregular periods.
I was found to have irregular uterine lining, most likely due to adenomyosis, and vertically oriented fallopian tubes on HSG (not sure why, tubes are not blocked). I was also found to have insulin resistance (HgbA1C 5.8, now on Metformin), and hypothyroidism (TSH 4.28, now on levothyroxine), and low Vitamin D (19, now on Vitamin D supplements). My husband and I are also taking prenatal/men’s multivitamin, Ubiquinol, and Omega-3.
We were offered two options: IUI and IVF. We have decided to pursue IVF given the very low AMH and our dream of having 3 live children. We think that pursuing IVF for embryo banking is the best option to achieve our dream of multiple children…
Our question is, what do you recommend as our IVF protocol? I have read about your mini-IVF protocol. Is mini-IVF protocol what I should consider? Do you recommend that I take DHEA?
Thank you!