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.
Dear dr sher. Im hoping to ask you about my early pregnancy hcg’s. Im worried about miscarriage with these numbers as follows:
15/08 – 212
18/08 – 689
20/08 – 1640
25/07 – 2654
As you can see, hcg was doubling nicely except for the last blood test. I should be 6 weeks tomorrow. Is there any hope? What is the likely reason for this? Embryo defect? What testing do you recommend please? Thanks .
It is probably OK but it is time for an US to provide clarity.
Geoff Sher
Dear Dr. Sher
I have 1 copy of mthfr gene with a homocysteine level of around 13 & pcos . I read somwehere that a level over 10 can increase risk of miscarriage by 38%!
I was told by my RE that the latest study showed
the opposite & that it did not cause miscarriage & no blood thinner is needed. I’m conflicted. Would you recommed a baby aspirin or orher medication?
Regards
Maria
Thrombophilia (Hereditary Clotting Defect) is defined as the genetic predisposition to developing intravascular thrombosis. It is due to hypercoagulability of blood leading to impairment of initial vascularization that takes place during implantation.
Thrombophilia affects as many as one in five people in the United States and is responsible for pregnancy loss (most particularly after the 1st trimester) and “unexplained” infertility, as well as being a factor in some cases of “unexplained” IVF failure. Whether (and/or the extent to which) thrombophilia causes 1st trimester recurrent pregnancy loss (RPL) is the subject of debate and is controversial. In fact, first-trimester RPL is far more likely to be due to immunologic implantation dysfunction (IID) and/or irregularities in the contour of the uterine cavity or insufficient thickness of its lining (a thin endometrium). Thrombophilia has also been associated with late pregnancy-induced complications such as preeclampsia, premature separation of the placenta (abruptio placenta), placental insufficiency with intrauterine growth retardation, and in “unexplained” intrauterine death.
This having been said, it is a fact that most women with a thrombophilia go on to experience healthy pregnancies.
Diagnosis of Throbophilia
Thrombophilia is diagnosed when one or more of the following is detected:
•Mutational defect involving methylenetetrahydrofolate reductase (MTHFR), which occurs in at least 20% of affected cases. Homozygosity for a common C677T mutation in the MTHFR gene that is associated with hyperhomocysteinemia is the most common form of hereditary thrombophilia leading to a 3-fold increase in risk of complications.
•Mutation of factor V Leiden (FVL),
•A mutation of prothrombin G20210A,
•Deficiency of antithrombin III
•Deficiency of protein C
•Deficiency of protein S
Risk Factors
•Pregnant women with predisposing factors such as:
•A personal or family history of thromboembolism (deep vein thrombosis), pulmonary embolism (blood clot in the lung), cerebrovascular accidents (i.e. strokes)
•A personal history of pregnancy complications such as unexplained intrauterine death, preeclampsia, abruptio placenta, intrauterine growth retardation, placental insufficiency, should be tested for the condition.
Treatment
Treatment should be initiated as soon as possible after pregnancy is diagnosed biochemically (blood or urine hCG test) and be continued throughout gestation.
Severe thrombophilias (e.g. homozygous MTHFR mutations, protein C deficiency, prothrombin G20210A mutation) as well as cases of mild thrombophilias associated with one or more of the pregnancy complications mentioned above, are best treated with low-molecular weight heparin (LMWH).
For other (milder) thrombophilias and no history of prior pregnancy complications: Low-dose aspirin with the B vitamins folic acid, B6 and B12.
Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
Julie Dahan
•Email: Julied@sherivf.com
•Phone: 702-533-2691
?800-780-7437
Geoff Sher
I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.
Dear Dr Sher,
If a protocol you use produces good numbers of eggs, does that mean it is the right one? surely if you get a good response in regards to mature egg numbers on collection day, does that actual type of protocol (long down/against/antagonist) really matter? I have gotten good numbers for my egg freeze collections. How do you know if it’s right for you?
It is one important factor but not the only one. Ultimately it is egg/embryo “competency” that matters most!
The potential for a woman’s eggs to undergo orderly development and maturation, while in large part being genetically determined can be profoundly influenced by the woman’s age, her “ovarian reserve” and proximity to menopause. It is also influenced by the protocol used for controlled ovarian stimulation (COH) which by fashioning the intra-ovarian hormonal environment, profoundly impacts egg development and maturation.
After the menarche (age at which menstruation starts) a monthly process of repeatedly processing eggs continues until the menopause, by which time most eggs will have been used up, and ovulation and menstruation cease. When the number of eggs remaining in the ovaries falls below a certain threshold, ovarian function starts to wane over a 5 to10-years. This time period is referred to as the climacteric. With the onset of the climacteric, blood Follicle Stimulating Hormone (FSH) and later also Luteinizing Hormone (LH) levels begin to rise…. at first slowly and then more rapidly, ultimately culminating in the complete cessation of ovulation and menstruation (i.e. menopause).
One of the early indications that the woman has entered the climacteric and that ovarian reserve is diminishing DOR) , is the detection of a basal blood FSH level above 9.0 MIU/ml and/ or an AMH level og <2.0ng/ml.
Prior to the changes that immediately precede ovulation, virtually all human eggs have 23 pairs (i.e. 46) of chromosomes. Thirty six to forty hours prior to ovulation, a surge occurs in the release of LH by the pituitary gland. One of the main e purposes of this LH surge is to cause the chromosomes in the egg to divide n half (to 23 in number) in order that once fertilized by a mature sperm ends up having 23 chromosomes) the resulting embryo will be back to having 46 chromosomes. A “competent” mature egg is one that has precisely 23 chromosomes, not any more or any less. It is largely the egg, rather than the sperm that determines the chromosomal integrity of the embryo and only an embryo that has a normal component of 46 chromosomes (i.e. euploid) is “competent” to develop into a healthy baby. If for any reason the final number of chromosomes in the egg is less or more than 23 (aneuploid), it will be incapable of propagating a euploid, “competent” embryo. Thus egg/embryo aneuploidy (“incompetence”) is the leading cause of human reproductive dysfunction which can manifest as: arrested embryo development and/or failed implantation (which often presents as infertility), early miscarriage or chromosomal birth defects (e.g. Down’s syndrome). While most aneuploid (“incompetent”) embryos often fail to produce a pregnancy, some do. However, most such pregnancies miscarry early on. On relatively rare occasions, depending on the chromosome pair involved, aneuploid embryos can develop into chromosomally defective babies (e.g. Down’s syndrome).
Up until a woman reaches her mid- thirties, at best, 1:2 of her eggs will likely be chromosomally normal. As she ages beyond her mid-thirties there will be a a progressive decline in egg quality such that by age 40 years only about 15%-20% of eggs are euploid and, by the time the woman reaches her mid-forties, less than 10% of her eggs are likely to be chromosomally normal. While most aneuploid embryos do appear to be microscopically abnormal under the light microscope, this is not invariably so. In fact, many aneuploid embryos a have a perfectly normal appearance under the microscope. This is why it is not possible to reliably differentiate between competent and incompetent embryos on the basis of their microscopic appearance (morphologic grade) alone.
The process of natural selection usually precludes most aneuploid embryos from attaching to the uterine lining. Those that do attach usually do so for such only a brief period of time. In such cases the woman often will not even experience a postponement of menstruation. There will be a transient rise in blood hCG levels but in most cases the woman will be unaware of even having conceived (i.e. a “chemical pregnancy”). Alternatively, an aneuploid embryo might attach for a period of a few weeks before being expelled (i.e. a “miscarriage”). Sometimes (fortunately rarely) an aneuploid embryo will develop into a viable baby that is born with a chromosomal birth defect (e.g. Down’s syndrome).
The fact that the incidence of embryo aneuploidy invariably increases with advancing age serves to explain why reproductive failure (“infertility”, miscarriages and birth defects), also increases as women get older.
It is an over-simplification to represent that diminishing ovarian reserve as evidenced by raised FSH blood levels (and other tests) and reduced response to stimulation with fertility drugs is a direct cause of “poor egg/ embryo quality”. This common misconception stems from the fact that poor embryo quality (“incompetence”) often occurs in women who at the same time, because of the advent of the climacteric also have elevated basal blood FSH/LH levels and reduced AMH. But it is not the elevation in FSH or the low AMH that causes embryo “incompetence”. Rather it is the effect of advancing age (the “biological clock”) resulting a progressive increase in the incidence of egg aneuploidy, which is responsible for declining egg quality. Simply stated, as women get older “wear and tear” on their eggs increases the likelihood of egg and thus embryo aneuploidy. It just so happens that the two precipitating factors often go hand in hand.
The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by those IVF practitioners who use a “one-size-fits-all” approach to ovarian stimulation. My experience is that the use of individualized/customized COS protocols can greatly improve IVF outcome in patients at risk – particularly those with diminished ovarian reserve (“poor responders”) and those who are “high responders” (women with PCOS , those with dysfunctional or absent ovulation, and young women under 25 years of age).
While no one can influence underlying genetics or turn back the clock on a woman’s age, any competent IVF specialist should be able to tailor the protocol for COS to meet the individual needs of the patient.
During the normal ovulation cycle, ovarian hormonal changes are regulated to avoid irregularities in production and interaction that could adversely influence follicle development and egg quality. As an example, small amounts of androgens (male hormones such as testosterone) that are produced by the ovarian stroma (the tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa cells (cells that line the inner walls of follicles), and egg maturation.
However, over-production of testosterone can adversely influence the same processes. It follows that protocols for controlled ovarian stimulation (COS should be geared toward optimizing follicle growth and development (without placing the woman at risk from overstimulation), while at the same time avoiding excessive ovarian androgen production. Achievement of such objectives requires a very individualized approach to choosing the protocol for COS with fertility drugs as well as the precise timing of the “trigger shot” of hCG.
It is important to recognize that the pituitary gonadotropins, LH and FSH, while both playing a pivotal role in follicle development, have different primary sites of action in the ovary. The action of FSH is mainly directed towards the cells lining the inside of the follicle that are responsible for estrogen production. LH, on the other hand, acts primarily on the ovarian stroma to produce male hormones/ androgens (e.g. androstenedione and testosterone). A small amount of testosterone is necessary for optimal estrogen production. Over-production of such androgens can have a deleterious effect on granulosa cell activity, follicle growth/development, egg maturation, fertilization potential and subsequent embryo quality. Furthermore, excessive ovarian androgens can also compromise estrogen-induced endometrial growth and development.
In conditions such as polycystic ovarian syndrome (PCOS), which is characterized by increased blood LH levels, there is also increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often a feature of this condition. The use of LH-containing preparations such as Menopur further aggravates this effect. Thus we recommend using FSH-dominant products such as Follistim, Puregon, and Gonal-F in such cases. While it would seem prudent to limit LH exposure in all cases of COS, this appears to be more vital in older women, who tend to be more sensitive to LH
It is common practice to administer gonadotropin releasing hormone agonists (GnRHa) agonists such as Lupron, and, GnRH-antagonists such as Ganirelix and Orgalutron to prevent the release of LH during COS. GnRH agonists exert their LH-lowering effect over a number of days. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in the LH level falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. GnRH Antagonists, on the other hand, act very rapidly (within a few hours) to block pituitary LH release, so as achieve the same effect.
Long Agonist (Lupron/Buserelin) Protocols: The most commonly prescribed protocol for Lupron/gonadotropin administration is the so-called “long protocol”. Here, Lupron is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH level, which is rapidly followed by a precipitous fall to near zero. It is followed by uterine withdrawal bleeding (menstruation), whereupon gonadotropin treatment is initiated while daily Lupron injections continue, to ensure a “low LH” environment. A modification to the long protocol which I prefer using in cases of DOR, is the Agonist/Antagonist Conversion Protocol (A/ACP) where, upon the onset of a Lupron-induced bleed , this agonist is supplanted by an antagonist (Ganirelix/Cetrotide/Orgalutron) and this is continued until the hCG trigger. In many such cases I supplement with human growth hormone (HGH) to try and further enhance response and egg development.
Lupron Flare/Micro-Flare Protocol: Another approach to COS is by way of so-called “(micro) flare protocols”. This involves initiating gonadotropin therapy simultaneous with the administration of GnRH agonist (e.g. Lupron/Buserelin). The intent here is to deliberately allow Lupron to elicit an initial surge (“flare”) in pituitary FSH release in order to augment FSH administration by increased FSH production. Unfortunately, this “spring board effect” represents “a double edged sword” because while it indeed increases the release of FSH, it at the same time causes a surge in LH release. The latter can evoke excessive ovarian stromal androgen production which could potentially compromise egg quality, especially in older women and women with PCOS, whose ovaries have increased sensitivity to LH. I am of the opinion that by evoking an exaggerated ovarian androgen response, such “(micro) flare protocols” can harm egg/embryo quality and reduce IVF success rates, especially in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe them at all.
Estrogen Priming – My approach for “Poor Responders” Our patients who have demonstrated reduced ovarian response to COS as well as those who by way of significantly raised FSH blood levels are likely to be “poor responders”, are treated using a “modified” long protocol. The approach involves the initial administration of GnRH agonist for a number of days to cause pituitary down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, the dosage of GnRH agonist is drastically lowered and the woman is given twice-weekly injections of estradiol for a period of 8. COS is thereupon initiated using a relatively high dosage of FSH-(Follistim, Bravelle, Puregon or Gonal F) which is continued along with daily administration of GnRH agonist until the “hCG trigger.” By this approach we have been able to significantly improve ovarian response to gonadotropins in many of hitherto “resistant patients”.
The “Trigger”: hCG (Profasi/Pregnyl/Novarel) versus Lupron: With ovulation induction using fertility drugs, the administration of 10,000U hCGu (the hCG “trigger”) mimics the LH surge, sending the eggs (which up to that point are immature (M1) and have 46 chromosomes) into maturational division (meiosis) This process is designed to halve the chromosome number , resulting in mature eggs (M2) that will have 23 chromosomes rather that the 46 chromosomes it had prior to the “trigger”. Such a chromosomally normal, M2 egg, upon being fertilized by mature sperm (that following maturational division also has 23 chromosomes) will hopefully propagate embryos that have 46 chromosomes and will be “:competent” to propagate viable pregnancies. The key is to trigger with no less than 10,000U of hCGu (Profasi/Novarel/Pregnyl) and if hCGr (Ovidrel) is used, to make sure that 500mcg (rather than 250mcg) is administered. In my opinion, any lesser dosage will reduce the efficiency of meiosis, and increase the risk of the eggs being chromosomally abnormal. . I also do not use the agonist (Lupron) “trigger”. This approach which is often recommended for women at risk of overstimulation, is intended to reduce the risk of OHSS. The reason for using the Lupron trigger is that by inducing a surge in the release of LH by the pituitary gland it reduces the risk of OHSS. This is true, but this comes at the expense of egg quality because the extent of the induced LH surge varies and if too little LH is released, meiosis can be compromised, thereby increasing the percentage of chromosomally abnormal and of immature (M1) eggs. The use of “coasting” in such cases (see below) can obviate this effect.
Severe Ovarian Hyperstimulation Syndrome (OHSS): Women with certain types of absent or dysfunctional ovulation as well as those who have polycystic ovarian syndrome (PCOS) are highly sensitive to gonadotropins and are at risk of developing OHSS. Such women are also more likely than others to produce poor quality eggs/embryos which, they are often led to believe is attributable to an intrinsic egg defect that is characteristic of their PCOS condition. This is not necessarily so. The most likely reason as to why many women with PCOS develop an excessive number of follicles and then go on to produce poor quality eggs/embryos has to do with the fact that, in an attempt to contain reduce the risk of OHSS they are often administered hCG prematurely – prior to the attainment of optimal egg maturation.
“Prolonged Coasting”: In the early nineties, we introduced “Prolonged Coasting”, a procedure which eliminates the risk of OHSS while allowing the hCG trigger to be deferred for long enough as to allow for optimal follicle/egg maturation to take place. Coasting involves withholding gonadotropin therapy while the administration of GnRH agonist/antagonist is continued. The daily measurement of blood estradiol is continued until the concentration drops below a safe threshold level, at which time HCG is administered (regardless of the number of follicles). When appropriately implemented “coasting” results in the production of good quality eggs/embryos, in circumstances where this might otherwise not have been possible.
Call 800780-7437 to set up a Skype consultation if you so wish.
Geoff Sher
Hello Dr Sher,
I fell pregnant twice in one year at age 36 both natural conception. First time I terminated by choice and again became pregnant 2 months later and miscarried early. My extreme guilt and regret for the termination meant I wanted the second pregnancy. My question is: does having been pregnant before, even if it wasn’t carried to term, make it more likely you will fall pregnant again at later stage rather than never having been pregnant at all?
Yes it does!
Geoff Sher
I have had 2 x LEEP procedures to remove high grade abnormal cells from my cervix. I discovered at age 32 that the procedures had scarred my cervix so I then had the scarring removed with surgery. I had been having regular unprotected intercourse for almost 4 years and never conceived until I had a saline sonohysterogram which was all clear (tubes, uterus) when I immediately became pregnant that cycle. It aborted and I had D&C of which the dilation led to the cervix becoming scarred over again & I have not conceived since. Since D&C and even before I have no fertile cervical mucus at ovulation & rarely ever have even a little. I have asked several fertility Drs if cervical scarring (I still had normal periods so not closed completely) could stop conception since menses blood comes out & they said that should mean sperm can still swim up. Does the scarring of cervix & subsequent loss of fertile mucus compromise the ability to conceive?
Many thanks,
Charlotte
Yes it does because cervical mucous is an essential part of the conception process. You will need intrauterine insemination.
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. IUI is a procedure that bypasses the cervix and places specially prepared sperm into a woman’s uterus around the time of natural or induced ovulation. The suggested advantage of IUI is that it shortens the path that sperm would normally take to a woman’s fallopian tubes.
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 in to 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 in vitro fertilization (IVF program), we began to recognize the potential advantage of washing and centrifuging raw semen, so as to separate sperm from the seminal fluid, and thereby remove prostaglandins that cause most of the problems. We subsequently introduced and, thereupon, became the first to publish on intrauterine insemination (IUI) in the Journal, Fertility and Sterility (April 1984).
Indications for Intrauterine Insemination (IUI)
•Artificial insemination using frozen (donor) 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 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 need to administer fertility drugs, such as Clomiphene, Pergonal, etc.
•Artificial insemination with partner’s sperm: In cases of sexual dysfunction (impotence, retrograde ejaculation, etc.) or timing issues, partner’s sperm may need to be collected and processed in preparation of IUI.
•Cervical mucus hostility: 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 antisperm antibodies. In all but the latter situations, 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 likely be ineffectual and should be replaced by in vitro fertilization (IV).
•Absent or dysfunctional ovulation: In some cases where the woman requires the use of fertility drugs to induce normal ovulation, the concomitant performance of IUI might improve pregnancy rates.
Selecting the Fertility Drugs for Intrauterine Insemination (IUI)
Clomiphene citrate (Serophene, Clomid): Clomiphene citrate is taken orally for 5 days starting on day 2 to 5 of the menstrual cycle. Ovulation will usually occur 10 days later. In some cases, hCG is used to trigger the ovulation but this is often unnecessary. Clomiphene is a relatively inexpensive and safe method for inducing ovulation and this is why it is so commonly prescribed to women undergoing IUI. However, women receiving clomiphene have about a one third lower pregnancy rate per cycle than is the case using injectible fertility drugs. but it there are draw-backs. Here are a few reasons why this is so:
1)Clomiphene citrate is an anti-estrogen. .Ordinarily normally ovulating women (without exposure to clomiphene) produce a single dominant follicle which produces enough estrogen to promote optimal cervical mucous production and an adequate endometrial lining (>9mm) However, with clomiphene is used to induce ovulation, its anti-estrogenic effect blunts this response. In fact on clomiphene,it requires much more estrogen to override this effect such that unless at least 3 large follicles develop so as to allow the blood estradiol levels to rise above 400pg/ml, cervical mucus production and endometrial development will usually be insufficient to allow a healthy pregnancy to occur. Younger women with normal ovarian reserve (Day-3 FSH of <9miu/ml) will usually produce >3 follicles where as women over 40 years of age and those (regardless of age) with diminished ovarian reserve will rarely do so and thus are very unlikely to achieve viable pregnancies on clomiphene
2)Clomiphene induction of ovulation is associated with a 15-20% chance of a condition called luteinized unruptured follicle (LUF) syndrome where the hormonal changes that precede and accompany and follow ovulation (including a rise in blood progesterone level) occur but this happens without ovulation occurring .LUF syndrome thus leads to the erroneous conclusion that an egg has been released when, in fact, it remains “trapped” in the ovarian follicle.
3)More than 3 consecutive (back to back) of clomiphene will result in a very significant increase in the anti-estrogen effects (referred to in 1&2 above), such that unless a break of at least 1 full menstrual cycle is taken, the likelihood of a viable pregnancy declines to less than 10%, regardless of the woman’s age or her ovarian reserve.
4)Increased production of Luteinizing Hormone: Clomiphene causes the pituitary gland to produce increased amounts of FSH and LH. FSH promotes follicle growth development while excess LH causes the ovary to produce male hormones such as testosterone. While a little testosterone is indispensable to follicle and egg development, too much testosterone can have the reverse effect and harm egg development. This effect is even more deleterious in women with diminished ovarian reserve (elevated FSH levels) and those over 40 whose ovaries tend to produce more testosterone-like hormones.
The following additional factors must be considered when it comes to the use of Clomiphene:
1)It is best not being prescribed for more than three consecutive months in a row to anyone and certainly not without taking a full cycle break before restarting a fourth cycle of treatment. The reason is that after the 3-4 consecutive months of clomiphene therapy, the anti-estrogenic properties are compounded to the effect of virtually converting it to an anti-fertility drug. This explains why >80% of successful clomiphene pregnancies occur within the first 3 months of treatment, and why the vast majority of clomiphene pregnancies that occur after >3 consecutive (back-to-back) cycles of treatment are lost (usually due to early miscarriages).
2)Clomiphene should not be used in women that have diminished ovarian reserve (e.g. women with elevated FSH levels) or in women over 40 years of age.
The good news is that upon discontinuation of Clomiphene for 4-6 weeks, adverse effects disappear, leaving the slate clean.
The real benefit of clomiphene lies in its oral route of administration, low incidence of side effects, and its low cost. The birth rate per clomiphene IUI is about 7-10% per cycle of treatment (about 1/3 lower than when injectible fertility drugs are used.
Letrozole(Femara): Letrozole, like clomiphene is an oral agent induces ovulation that causes the pituitary gland to release large amounts of FSH as well as LH. The advantage that Letrozole has over clomiphene is that unlike the latter, it is NOT anti-estrogenic and thus does not compromise development of the uterine lining or adversely affect the production of cervical mucus. However as is the case with clomiphene, Letrozole causes increased LH release that can lead to overproduction of male hormones (e.g. testosterone) by the ovaries with potentially adverse effect on egg/embryo quality.
Thus while Letrozole does have potential advantages over clomiphene, the exaggerated LH-induced testosterone effect, especially in women over 40 years of age and/or those with evidence of diminished ovarian reserve limits its value.
Gonadotropins (Menopur, Gonal-f, Folistim and Puregon:) Women with absent or abnormal ovulation who require fertility drugs in preparation for IUI should receive gonadotropins. Granted, these agents are more expensive than clomiphene, but they have no anti-estrogenic properties.
The birth rate with gonadotropin IUI in women under 35 years of age (in the absence of male infertility, where it is much lower) is about 10-15%. However, success is affected by, and contingent upon, the procedure being performed (1) for the correct indications, (2) avoiding the performance of IUI when contraindications exist (see below) and, (3) where the woman is ovulating normally on her own. Success rates decrease as a woman’s age advances. In women 35-40 years of age the birth rate is 5-10% per cycle and for over 40 years, the birth rate per cycle is under 2%, declining to less than 1% after age 43.
Relative Contraindications to Intrauterine Insemination (IUI)
Advancing age: A woman’s natural ability to conceive declines with age starting after age 30. It falls more rapidly after age 35 and then, precipitously so after 40. The main reason for this is that the percentage of eggs that become chromosomally abnormal (aneuploid) through “wear and tear” increases as she gets older, such that by age 40 an ovulated egg is probably 3 times less likely to be able to propagate a viable pregnancy than at age 30. This explains the fact that under 35, the normally ovulating woman who receives injectible fertility drugs to induce ovulation has about a 10-12% chance of having a baby. In comparison, after age 40, the same woman would have about a 2% chance. For this reason alone, IUI is best suited to women under 35 and, in my opinion, should NOT be undertaken after age 40. Ages between 35 and 40 represent a “gray area.”
Significant Male Infertility: Contrary to popular belief, the performance of IUI in cases of male infertility does not improve success rates over regular and well-timed intercourse alone. In vitro fertilization with intracytoplasmic sperm injection (IVF/ICSI) is the only method to optimize pregnancy rates in association with male refractory infertility.
Tubal damage
1.Post-Pelvic Inflammatory Disease (PID): It is very important to understand that Fallopian tubes are not mere “pipes” through which sperm, egg and embryo must pass to achieve an intrauterine pregnancy. They are vital and sophisticated organs that serve intricate functions in the reproductive process. They transport sperm in the direction of the ovary, while at the same time, the fimbriae (petal-like extrusions at the end of the tube) apply themselves to the area of the ovary from which the egg is ovulating in order to pick up the extruding egg, and carry it back down the tube towards the uterus. About one third of the way back, the egg encounters the sperm and fertilization occurs. Thereupon, the resulting embryo is transported to the uterine cavity where it hopefully will implant.
PID, the commonest cause of damaged Fallopian tubes will, unless it is diagnosed and effectively treated very early on, inevitably and permanently disrupt the sophisticated function and continuity of the inner lining of both Fallopian tubes. In more severe cases, the intricate muscular arrangement of the tubal wall is also damaged, compromising the time-sensitive and programmed migration of sperm, egg and embryo. In advanced cases of PID, the fimbria fuse, thus compromising egg pick-up, and ultimately blocking the tube(s) completely.
PID almost always affects both Fallopian tubes. Indeed, one tube might be more damaged than the other, but both will be affected to a greater or lesser degree. That is why, even if one tube remains or is surgically rendered patent, the problem of markedly reduced fertility and the increased risk of a subsequent tubal pregnancy remains an ever present risk and reality. Thus, the use of fertility drugs to induce ovulation, or the use of microsurgery to open Fallopian tubes and free surrounding adhesions are often not curative of infertility. Furthermore, in cases where a pregnancy follows, the result is often a tubal (ectopic) gestation. This also serves to explain the fact that the intrauterine pregnancy rate following ovulation induction (with or without concomitant IUI) is likely to be to be at least 10 times lower in women with PID, and why, when a pregnancy does ensue, it is 10 times more likely to be a tubal (ectopic).
Thus, in women who have had PID, IVF is the only way to safely bypass the “damaged plumbing” and initiate a viable intrauterine pregnancy.
2.Post-Tubal Ligation. In large part, the same holds true following successful reconnection of previously ligated (tied) Fallopian tubes. The reason is that even with successful surgical reestablishment of tubal patency, there is always a degree of shortening of the tube(s) or a degree of damage due to surgical scarring of the inner lining of the tube(s). Even when tubes are normal, the birth rate per IUI cycle is about 10%, and following any form of tubal damage (PID or surgically-induced) the success is 5-10 times lower per IUI cycle (i.e. 1%-2%). Hence, IUI can hardly be justified in such cases, and IVF becomes the only effective and viable option.
Endometriosis:
While the exact cause of endometriosis remains an enigma, it is now apparent that immunologic dysfunction is a significant feature of this disease, and that a toxic environment exists in the pelvis (surrounding the tubes and ovaries) in patients with this condition. As a consequence, ovulation – whether spontaneous or induced by fertility drugs – commits the egg to pass through a toxic pelvic environment in order 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.”
In spite of these anti-fertility influences, many women with mild endometriosis do in fact 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 can anticipate about a 40% chance of conceiving on their own within two or three years (contingent upon their ovulating normally and having a fertile male partner). The occurrence of pregnancy in the latter cases occurs in spite of, rather than due to, such treatment. Such women may consider deferring any invasive treatments in favor of a “wait-and-see” approach. Conversely, women over the age of 35 whose egg quality is inevitably on the decline, IVF offers the only rational approach.
Fertility Drugs and Multiple Births
Normally ovulating women usually develop a number of follicles (fluid filled spaces within the ovary (ies) that contain eggs and produce estrogen) during the first week of the menstrual cycle. All but one (and sometimes two) of the follicles fail to develop to the point of being eligible for ovulation. The process is known as Selection. It is important to recognize that in all normally ovulating women, the one or two follicles selected to ovulate will inevitably be larger than the remaining follicles, regardless of whether the woman is receiving fertility agents such as Clomiphene or Pergonal, etc. 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 no not have a greater incidence of high order multiple pregnancies. In contrast, women who do not ovulate at all, and those who ovulate irregularly or dysfunctional do not have the ability to select one or two dominant follicles for ovulation. As such, following the administration of fertility drugs for ovarian stimulation, numerous follicles may develop at the same rate, and several eggs can be ovulated simultaneously. This translates into a greater chance of pregnancy, but also 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 abnormal 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 in vitro fertilization (IVF), where the number of potential babies can be limited by the number of embryos transferred to the uterus.
It is indeed unfortunate that fertility treatment has become so regimented that most patients find themselves being ushered through a scripted treatment process. As an example, clomiphene, though favored for its convenience and low cost, does NOT yield the same success as IUI with gonadotropin stimulation. In fact the per-cycle success rate of IUI using clomiphene is about 30% less. Also, women with endometriosis (regardless of severity) have much lower success with IUI (see above). Women over age 40 have such a low success with IUI that they cannot afford the time wasted in the process. Such women need IVF.
For the majority of couples who require an individualized strategic plan of action at an early stage, such an approach is emotionally, physically, and financially draining, leaving them both suspicious and critical of the intent of the medical profession.
The introduction of inexpensive Micro-IVF changes the landscape. In fact, the success rate is three times higher than with IUI. This plus the low the relatively low cost of Micro-IVF (as compared with conventional IVF) is a major advantage of the approach.
Good luck!
Geoff Sher
In that case could I benefit from the simple use of something like “preseed” lubricant which has been created to act in the same manner as natural fertile cervical mucus? This product has resounding success and is widely lauded on chat forums by women worldwide who swear it works very well, and in many cases on the very first try! I would like to avoid any further entry and trauma to my cervix, so IUI is something I’d prefer to avoid.