Progesterone Supplementation

Progesterone is initially produced by the corpus luteum, a small structure formed on the ovary when the egg is released from the ovarian follicle. After about twelve weeks, the placenta begins to produce progesterone. Progesterone is vital to pregnancy support because it causes increased vascularization (greater blood flow) and thickening of the endometrium, which is the inner layer of the uterus. If pregnancy does not occur, progesterone levels fall triggering menstruation. Menstruation is essentially "shedding" of the endometrial lining of the uterus. These processes increase the ability of the endometrium to provide vital nutrients to the developing embryo.
Progesterone is responsible for the temperature rise that is measured by the basal body temperature chart. Progesterone is sometimes used to treat a "luteal phase defect". The luteal phase is the period between ovulation and menses. Insufficient production of progesterone by the corpus luteum might not provide adequate stimulation of the endometrium to support a pregnancy. An endometrial biopsy is often taken to document a luteal phase defect.
Progesterone is used in in vitro fertilization cycles to insure adequate development of the endometrium. The injectable form of progesterone(Gestone) provides the most predictable blood levels and is often used in IVF. It is administered by intramuscular injection and is painful. Some clinics are now using a gel form (Crinone) which is administered intravaginally or specially compounded suppositories may be prescribed.
In some women the ovaries do not make enough progesterone or the lining of the uterus does not respond well to normal amounts of progesterone. If this happens the lining of the uterus is not able to thicken or prepare for implantation of the fertilized egg. This may result in the failure of the fertilized egg to implant and pregnancy does not occur. There are many reasons why the ovaries might not produce enough progesterone. The different causes may be ovulation problems, endometriosis, fertility drugs, or "older eggs".
Progesterone supplementation is a medication that is taken after ovulation and it corrects the low progesterone hormone imbalance. The lining of the uterus responds to the progesterone medication, it thickens and prepares for the implantation and support of a pregnancy. A woman will continue to use progesterone until the placenta has developed and is able to support the pregnancy. (11-13 weeks after conception).
Progesterone supplementation can be given in the form of vaginal suppositories, injections (shots) or by mouth. The progesterone is usually started four days after you have had the shot that causes ovulation to occur (hCG or Profasi). You will continue the progesterone until you have had a negative pregnancy test or a normal menstrual period. If you conceive and are pregnant you will continue the medication for several weeks; the doctor will tell you when it is time to stop. Progesterone supplementation has few side effects. These may include breast tenderness, nausea, fatigue, or a 2-3 day delay in the start of your period.
The medication may be packaged with a patient information insert. The purpose of this insert is to provide information about progesterone to all patients taking it. The information in the insert pertains to all progesterone medication, both natural and synthetic. There is an increased risk of birth defects to babies exposed during pregnancy to synthetic progesterone. However, the progesterone supplementation prescribed by the physician is in a natural form and this does not increase the risks of birth defects. Please talk with your physician if you have any concerns.
Progesterone Suppositories are inserted into your vagina and are then absorbed by the body. You may notice some leakage of the medicine from your vagina when you are up and moving around. Do not worry about this because the medication is still being absorbed. You may want to wear a panty liner to protect your clothing. There are no activity restrictions while using the suppositories, including sex. It probably would be more comfortable to wait until after intercourse before inserting the suppository. Occasionally the leakage of the medicine can be irritating to the skin around your vagina; contact your physician if the vaginal irritation becomes too bothersome.Progesterone Oral Medication comes in several different forms that are taken by mouth. Progesterone Injections are "shots" that are injected into your muscle (usually the buttocks or thigh) and the progesterone is absorbed by your body. You may notice soreness or tenderness at the injection site while you are taking the progesterone shots. After an injection you may apply an ice-pack to the area for relief. Please contact your physician if the injections become too painful.
Progesterone has many other uses not related to infertility treatment some of which have dubious scientific support.A qualified physician should be personally consulted prior to the administration of any hormone product.

Letrozole for Ovulation Induction

Ovulatory dysfunction is one of the most common causes of reproductive failure in subfertile and infertile couples. Since the first clinical trial was published in 1961, clomiphene citrate (CC) has been the front-line therapy for ovulation induction. Its use quickly expanded to other empiric indications, such as luteal phase defect and the enhancement of fecundity in unexplained infertility. Failure to respond to CC occurs in up to 20% of cases, which may then require the use of injectable gonadotropins. The drawbacks of this approach are its high cost (both for the medication and the extensive monitoring it requires), risk of the potentially life-threatening ovarian hyperstimulation syndrome (OHSS), and, perhaps most importantly, the significant risk of high-order multiple gestations. Clearly, an inexpensive yet equally efficacious oral alternative would be ideal. Recent research has focused on the successful use of aromatase inhibitors, mainly letrozole, for ovulation induction. The Rotunda medical team have begun incorporating letrozole into treatment plans for appropriately selected patients.

CC is an estrogen-receptor (ER) modulator. It binds to nuclear ER in the hypothalamus, mitigating the usual negative feedback of estrogen on GnRH during the follicular phase. This results in augmented FSH stimulation to the ovary from the pituitary as a result of changes in GnRH pulsatility and is the mechanism for ovulation induction or enhancement. Unfortunately, CC can bind nuclear ER for an extended period of time (6-8 weeks) and eventually depletes ER in other estrogen-dependent tissues, such as the endometrium and cervix. This leads to diminished endometrial development and decreased cervical mucus production. When used in the early follicular phase, letrozole inhibits estrogen synthesis, thereby causing enhanced GnRH pulsatility and consequent FSH and inhibin stimulation. This results in normal or enhanced follicular recruitment without the risk of multiple ovulation and OHSS. Letrozole has a very short half-life (~45 hours) and, therefore, is quickly cleared from the body. For this reason, it is less likely to adversely affect the endometrium and cervical mucus.

Letrozole has also been shown to improve outcome in cycles combining injectable FSH with oral ovulation induction. Recent studies report that the combination of letrozole and FSH enhances follicular recruitment while reducing the amount of FSH needed for optimal stimulation, ultimately reducing the cost of the cycle. This approach has also been useful in patients who previously responded poorly to superovulation treatment protocols.

The usual dose for letrozole ovulation induction is 2.5 mg on cycle days 3-7. Ongoing research using a single dose (10-30mg) on cycle day 3 shows similar rates of ovarian stimulation. Single doses as high as 60 mg have been administered without negative effects. Potential side effects of estrogen depletion, including hot flashes, nausea, and vomiting, have been reported in older breast cancer patients who were given the medication on a daily basis for several months. When used in a healthy population for a short time, the medication is much more tolerable. The pregnancy outcomes for letrozole ovulation induction have been very encouraging. The results of several studies show that letrozole and letrozole + FSH cycles had the highest pregnancy rates of studied regimens, and that letrozole cycles had the lowest multiple gestation rate.

Research into the role of aromatase inhibitors in fertility treatment is ongoing. As with any new course of treatment, it will be important to study long-term effects on the patient, the pregnancy and the conceived children. Due to their short half-life, it is unlikely that letrozole or other aromatase-inhibitors will be associated with any significant negative effects.

Antisperm Antibody Test

Antisperm antibodies (anti-spermatozoa antibodies, sperm antibodies) in the form of autoantibodies in male and alloantibodies in female patients directed against sperm antigens may prevent fertilization of the oocyte into the female genital tract and are therefore one of the major reasons for an immunologically induced infertility. Fertility disorders of unknown etiology of male as well as female patients result to a considerably amount (up to 20%) from antisperm antibodies.

An antisperm antibody test looks for special proteins (antibodies) that fight against a man's sperm in blood, vaginal fluids, or semen. The test uses a sample of sperm and adds a substance that binds only to affected sperm. Semen can cause an immune system response in either the man's or woman's body. The antibodies can damage or kill sperm. If a high number of sperm antibodies come into contact with a man's sperm, it may be hard for the sperm to fertilize an egg. The couple has a hard time becoming pregnant. This is called immunologic infertility.

A man can make sperm antibodies when his sperm comes into contact with his immune system. This can happen when the testicles are injured or after surgeries (such as a biopsy or vasectomy) or after a prostate gland infection. The testicles normally keep the sperm away from the rest of the body and the immune system. A woman can have an allergic reaction to her partner's semen and make sperm antibodies. This kind of immune response is not fully understood but may affect fertility. This is a rare cause of infertility.

The antisperm antibody test may be done if:a)A cause for infertility cannot be found. Experts disagree about the usefulness of the test because the result may not change the treatment. b)The results from another fertility test, such as the postcoital test, are not clear.

To do the test in women, a blood sample is taken from a vein in the arm. For men, a semen sample is collected after the blood samples are taken. You should not release your sperm (ejaculate) for 2 days before the test. It is important to not go longer than 5 days before the test without ejaculating.

The husband's sperm is tested for the presence of antisperm antibodies in the Direct ASAB Test. The husband should avoid ejaculation for a period of two to five days before his scheduled test. For the Indirect ASAB Test blood is drawn from the husband and/or wife and the serum is isolated from the blood. The serum is tested indirectly for the presence of antibodies to sperm by incubating it with donor sperm in the Indirect ASAB Test. If antisperm antibodies are present in the serum, they will attach to the donor sperm and cause a positive test result.

Your doctor may request the Immunobead Antisperm Antibody Test for a variety of reasons. These include a Semen Analysis which shows sperm agglutination (sticking together), a Post-Coital Test (PCT) which is abnormal, or unexplained infertility. This test is also a prerequisite for all IVF patients. Immunobeads are small beads that are treated with special proteins. If antibodies to sperm are present, these beads will attach to the sperm. One hundred motile (swimming) sperm are evaluated for bead attachment. For the male, if twenty or more of these sperm have beads attached to them (a result of 20% or greater), this is considered a positive test and indicates that antisperm antibodies may be present. For the female, a result greater than 10% is considered a positive test.

If the husband tests positive for ASAB, his semen specimen for IVF will be collected into a specimen cup containing a buffer solution that will minimize the effect of ASAB on the sperm. Normal IVF fertilization rates (fertilization of 50% or more of the mature eggs) are usually achieved with this treatment. When the female partner or both partners have tested positive for ASAB, or if the husband also has a compromised semen specimen (low count, low motility or low SPA), fertilization rates may be lower and your physician may suggest ICSI.

Seasons Greetings

Acupuncture Bad For IVF Success

Contrary to the widely held belief that acupuncture enhances a woman's chances of successfully becoming pregnant whilst undergoing IVF treatment, a study at the University of Oklahoma found that women who combine acupuncture and IVF were 37 per cent less likely to conceive than those who underwent IVF treatment alone. The new findings caused head researcher Dr LaTasha Craig, to warn that acupuncture should not be recommended until further research has been conducted to resolve the discrepancy between this study and earlier research. Previous studies had appeared to indicate a marginal increase in IVF efficacy or showed no obvious benefit, allowing some to scientifically postulate that the ancient far eastern medical practice of acupuncture might somehow affect certain muscles and glands of the nervous system to help the
lining of the uterus become more receptive to embryo implantation.
The latest study evaluated the results of 97 patients with an average age of 35 who were randomly divided into two groups. One group received acupuncture for 25 minutes before and after embryo implantation. The pregnancy rate for the IVF group without acupuncture was 69.9 per cent compared to the 43.8 per cent less successful pregnancy rate for those who
received the two-pronged acupuncture 'therapy' approach. Dr Craig suggested that other factors may have counteracted any therapeutic effect of acupuncture such as the stress from undergoing acupuncture just before IVF or from travel in traffic to external acupuncture clinics and onto IVF appointments.
Some clinics regularly offer acupuncture with its IVF services, according to Mark Bovey from the British Acupuncture Council, who was alarmed by the results. Although the number of women who undergo IVF alongside acupuncture procedures has skyrocketed, many doctors believe that the placebo effect is a likely explanation for any perceived benefit.

Fertility Injections - A Waste of Time?

New research found that hormone injections to achieve pregnancy do not 'provide any added benefit' financially or medically in women under 40 as an alternative infertility treatment before advancing to IVF, announced head researcher Dr Richard Reindollar, from the Dartmouth-Hitchcock Medical Centre in New Hampshire, last week at the annual meeting of the American Society for Reproductive Medicine in Washington last week. The comprehensive study indicates that the thousands of Indian women each year who receive follicle-stimulating hormone (FSH) injections costing Rs 20,000 - Rs 25,000 per course for infertility treatment before resorting to IVF treatment may actually be prolonging the time it takes to become pregnant at unnecessarily increased costs and health risks than if they were to undergo IVF treatment straight away.
In the study of 503 infertile couples, those who were 'fast-tracked' to IVF treatment became pregnant three months earlier than those couples who underwent the daily injections together with artificial insemination (IUI) before, if unsuccessful, undergoing IVF treatment, which also involves ovary-stimulating injections but is coupled with the more invasive egg
extraction and embryo implantation procedures. In practice, women typically begin treatment by trying clomiphene pills together with IUI and when that is unsuccessful most Indian and many UK clinics then offer a course of injections with IUI before performing IVF as a final treatment stage. Both groups were initially unsuccessful with pills and IUI and both had a similar chance of becoming pregnant. Ultimately 78 per cent of those fast-tracked and 75 per cent of those receiving injections were successful but the fast-tracked couples had a 40 per cent increased chance to become pregnant
within the first eight months versus eleven months of treatment, and saved overall costs by an average of £5,000- reducing average payment from £35,700 to £30,750.
Women may also be placing themselves at prolonged health risk. The injections stimulate the ovaries egg production and have significant physical side-effects including headaches, abdominal pain and ovarian hyperstimulation syndrome, which in extremely rare cases can be fatal. They also increase the risk of multiple births by 20 to 30 per cent, which in turn increases the risk of birth defects and pregnancy-induced hypertension. Contrary to National Institute for Health and Clinical Excellence guidance, which recommends the NHS pay for hormone injections only for women with endometriosis, many private clinics offer them more generally often in cases of unexplained infertility, according to Mark Hamilton, chairman of
the British Fertility Society. Infertility affects one in seven British couples and Hamilton urges patients to carefully consider with their doctors the efficacy of infertility treatments before attempting treatments with lower success levels. Bill Ledger, Professor of Obstetrics and Gynaecology at the University of Sheffield felt this study adds to mounting evidence in
support of the cost-saving elimination of injections and redirection of those funds into providing cheaper IVF treatment with an equal success rate without the delay.

Investigating The Infertile Male

It is natural for the attention of the gynecologist and family practitioner to initially turn toward the female in cases of infertility. Although infertility is generally viewed a ‘female problem’, fully 45% of infertile couples have male infertility as a contributing cause. It makes sense then to begin the fertility evaluation with a basic evaluation of the male partner. Because significant male factor infertility is generally treated with in vitro fertilization, needless hysterosalpingograms, laparoscopies and clomiphene cycles can be avoided by early detection of significant dysfunction in the male partner. The savings of time and money can be tremendous. IVF with intracytoplasmic sperm injection (IVF/ICSI) has made it possible to successfully treat virtually all cases of male infertility, even with only a few moving sperm in the entire ejaculate.

The evaluation of the male partner starts with a competent semen analysis. Non-specialized laboratories, such as Ranbaxy and Metropolis, perform a World Health Organization (WHO) semen analysis. This is a crude screening test and should be replaced by the strict semen analysis (Kruger) that is done by most fertility centers. The difference between the WHO and the Kruger test is that, with the Kruger test, sperm morphology is evaluated in a very stringent manner. The results of the Kruger test predict fertilization rates in vitro and presumably in vivo as well. The WHO does not predict outcome and will frequently miss subtle but clinically significant sperm abnormalities. The cost of the Kruger test is the same or less than a WHO analysis at our center.

When male infertility is suspected and tests reveal abnormal semen parameters, the couple should be referred to a fertility physician and/or urologist for further evaluation. Conditions warranting referral for male infertility are: a sperm concentration of less than 20 million per mL, motility less than 35%, and morphology less than 5% (Kruger) or 30% (WHO).

A direct antisperm antibody test should be done in cases where the male has a history of genital trauma, genital surgery or has never initiated a pregnancy. The direct antibody test is done on a semen sample and detects whether antibodies are attached to the sperm themselves. The cutoff for a positive test varies between labs but is usually considered positive when greater than 10%-20% of sperm are bound. Couples with antisperm antibodies should be referred to a fertility physician for further evaluation and treatment.

Genetic evaluation of male infertility is indicated when there is a sperm concentration less that 5 million per milliliter. This male infertility evaluation should consist of a karyotype and a study to look for microdeletions on the long arm of the Y chromosome (Yq deletion study). An assay for DNA fragmentation in the sperm cells may also be helpful in select patients. If azoospermia is present, carrier status for one of the cystic fibrosis mutations should be ruled out. These men should, of course, be referred for a urological evaluation. If surgical treatment of the infertile male is not indicated, a fertility physician can then complete treatment.

Hormonal evaluation of the infertile male is indicated when there is a history of sexual dysfunction, azoospermia or abnormal physical findings. This workup, which consists of testosterone, FSH, LH and prolactin levels, should be accompanied by urological consultation.