Introduction

Sperm preparation methods developed for in-vitro fertilization and embryo transfer (IVF-ET), such as the wash, swim-up and swim-down techniques, and the use of density gradients, have led to a resurgence of interest in intrauterine insemination (IUI). The use of washed prepared sperm for IUI has also resulted in a significant reduction in the side effects associated with the use of neat semen for IUI (which never should be used), such as painful uterine cramps, collapse and infection. In view of the fact that IUI is a relatively simple procedure compared with in-vitro fertilization (IVF), its popularity as a treatment option for certain diagnostic groups of infertile couples is increasing, since it is intermediate between the simpler ovulation induction (OI) and the more “high tech” IVF. This is particularly so in developing countries, where facilities for IVF may be limited and the cost of treatment by IVF is a major issue.

The term “artificial insemination” (AI) covers a range of techniques for insemination: it may be intra-vaginal, intracervical, intrafallopian, intraperitoneal or intrauterine. AI has been used for many years for a number of different indications, and either the husband/partner's sperm (AIH) or donor sperm (AID) may be used. It is almost 200 years since John Hunter advised a man with hypospadias to inject his seminal fluid into his wife's vagina with a syringe, resulting in a normal pregnancy. In the nineteenth century, Sims artificially inseminated six women who had negative postcoital tests. He used their husbands' semen obtained from the vagina after intercourse; one pregnancy was achieved. The first reported case of human donor insemination was by William Pankhurst from Philadelphia in the United States in 1884.

Introduction

Insemination technique has changed greatly during the past 40 years, from a simple vaginal technique that was little different than that used by John Hunter in 1785 to intracervical (ICI), intrauterine (IUI), fallopian tube sperm perfusion (FSP) and direct intraperitoneal insemination (DIPI) techniques. When Nachtigall et al. reviewed the status of artificial insemination in 1979, nearly all inseminations were vaginal and pregnancy rates were generally satisfactory when donor sperm was used or insemination with partner sperm was performed because of physical problems, but very poor when insemination with partner sperm was performed because of low sperm count. The semen specimen was usually fresh for both donor and partner insemination, except in rare cases where multiple samples of poor-quality sperm were cryopreserved in the hope that sufficient “good” sperm would be available when the accumulated specimens were thawed. Those cases were nearly always unsuccessful.

Successful pregnancies following intrauterine insemination of 10 minims (0.6 mL) of fresh unprocessed sperm were reported in 1920, but the procedure was abandoned because of concern about infection. Furthermore, the amount inseminated had to be kept small to reduce uterine cramping, so it was not helpful in cases where the sperm count was low. When insemination techniques were compared in 1957, pregnancy rates for IUI were worse than when the entire sperm specimen was placed in a cervical cup applied to the cervix, or simply deposited in the vagina.

In the present day, insemination with both donor and partner semen is nearly always performed by the intrauterine insemination (IUI) technique.

Introduction

Ultrasound (US) is an essential part of infertility evaluation of the female, and is indispensable for obtaining optimal results from intrauterine insemination (IUI) and ovulation induction (OI). Use of US for evaluation and management of infertility is of recent origin. The first report of follicle changes throughout a complete menstrual cycle appeared in 1979. Sonohysterography (SHG), instillation of sonolucent fluid into the uterus in order to improve visualization of the fallopian tubes and soft tissue abnormalities of the uterine cavity, followed in 1984. Recent developments include the use of three-dimensional US to delineate uterine structural abnormalities, and the adoption of color Doppler blood-flow analysis of uterine and ovarian blood vessels.

Transabdominal ultrasound (AUS) is the preferred method for evaluation of pelvic masses larger than 5 cm, and for evaluation of the pregnant uterus after the first trimester. Transabdominal US requires a distended bladder, which is uncomfortable for the patient, particularly when pressure is applied on the lower abdomen during scanning. Accurate delineation of pelvic structures is not possible in all women due to beam scatter by excessive subcutaneous fat and overlying gas-filled bowel loops, or when the ovaries and uterus are located deep in the pelvis. Transabdominal US utilizes frequencies between 2.5 and 3.5 MHz. As frequency is increased, imaging depth decreases and ambiguity occurs because of attenuation. For soft tissue, attenuation in decibels (dB) is approximately 0.5 dB per cm for each MHz of frequency.

Introduction

The semen analysis (SA) in the form in which it appears today is a relatively recent invention. The definition of a “normal” semen analysis was not standardized until publication of the World Health Organization (WHO) Laboratory Manual for the Examination of Human Semen and Sperm–Cervical Mucus Interactions in 1980. Between 1869, when Sims reported that sperm needed to be present in cervical mucus for conception to occur, and 1951, the Sims–Huhner postcoital test and the presence of motile sperm on a microscopic slide were considered the only tests necessary to evaluate male fertility. The postcoital test was used as part of their initial evaluation of infertile couples by 92% of infertility specialists in private practice in the United States according to a survey taken in 1998. Examination of a droplet of ejaculate under the microscope remains a highly accurate, easy-to-perform “qualitative” test of male fertility.

In 1951, MacLeod and Gold analyzed the sperm counts of 1,000 fertile and 1,000 infertile men stratified at intervals of 20 × 106/mL. They observed that 19% of infertile men had counts of less than 20 × 106/mL, compared to 8% of fertile men. On this basis they stated that men with sperm counts above 20 × 106/mL were fertile, and men with counts below that concentration were subfertile, even though they had not further stratified counts of less than 20 × 106.

Introduction

Donor insemination is the only insemination procedure performed by many physicians. It is convenient, easy to perform and requires no special equipment. Unwashed donor sperm can be purchased from commercial sperm banks “ready to use.” Commercial sperm banks usually provide specimens in screw-topped polypropylene cryovials containing 10–30 × 106 motile sperm after thaw in 1 mL media. Specimens may be either prewashed for intrauterine insemination (IUI) or unwashed for vaginal (IVI) or intracervical insemination (ICI). Unwashed specimens can also be used for IUI after they are washed by the recipient clinic. Specimens may also be provided in straws in 0.5 mL of media.

Unwashed specimens need only to be thawed at room temperature or in warm water for 5–10 minutes to be ready for IVI and ICI. IUI specimens require centrifugation to remove the cryoprotectant, even if they were prewashed. Because liquid nitrogen (LN2) is extremely hazardous if spilled, specimens are usually “dry” shipped in smaller versions of the Dewar LN2 tanks used for long-term storage (Fig. 12.1). Dry-shipping tanks contain small amounts of LN2 at the bottom sufficient to maintain the temperature of vials or straws suspended in LN2 vapor at −180°C for 10–12 days from the date the shipper was filled. Sperm specimens that can not be used within this time may be transferred to regular larger LN2 tanks for long-term storage. A few commercial banks still ship donor sperm in dry ice overnight for use the next day.

Introduction

The incidence of female infertility is age- and parity-related. In a national government survey conducted in 2002, 7.4% of all married women in the United States, aged 15–44, reported difficulty becoming pregnant during the previous year. The incidence of infertility ranged from a low of 4% in previously pregnant women aged under 30, to 27% in never-pregnant women aged 40–44. In a previous survey of the same population, 35% of women who sought medical help were treated with ovulation induction (OI), 13% with husband or donor intrauterine insemination (IUI) and 1.7% with in-vitro fertilization (IVF) or other advanced assisted reproductive technology (ART). Similar infertility rates are reported elsewhere in the Western world, with the availability of infertility treatment facilities and the use of IVF varying both between and within countries. In 2003, IVF was responsible for 6.5% of live births in Denmark and 3% of all live births in Europe, compared to 1.2% of live births in the United States. Patients in the United States with private health insurance were four times more likely to receive OI and three times more likely to have IUI than patients without insurance, but no more likely to have IVF than patients without insurance.

The causes of infertility in 14,141 couples, from reports compiled in 1995, were ovulatory disorder 27%, abnormal semen 25%, tubal occlusion 22%, endometriosis 5% and unexplained 17%.

Th is manual is intended for the general or family practitioner, as well as for gynecologists and specialists in infertility treatment. While treatment by in-vitro fertilization (IVF) and other advanced techniques attract the most attention and shape the public perception of infertility treatment, far more infertile couples achieve pregnancies with ovulation induction (OI) or combined ovarian stimulation and intrauterine insemination (IUI), the two techniques described in detail in this book, and which form the first line of infertility treatment. Moreover, they can be performed in almost any office or clinic, thus allowing patients to be treated by physicians and nurses already familiar with their general health, without the need to travel to distant specialty clinics. Many practitioners believe, from their time in training, that evaluation of infertile couples is too time-consuming and unrewarding, and that treatment is too complex to be part of their general or obstetric and gynecological practices. Nothing could be further from the truth. Infertility should be viewed, not as a diagnosis, but as a symptom of an underlying medical problem, affecting either one or both partners, which, if left untreated, will eventually affect their general health and emotional well-being.

Multiple births

All multiple births are associated with significant neonatal, maternal and family morbidity, but this is particularly so for triplet and higher-order multiple births (HOMB). Ovulation induction (OI), outside of in-vitro fertilization (IVF), is estimated to be responsible for 20% of twins, 40% of triplets and 70% of infants live born in quadruplet and higher-order deliveries in Western nations. On average 10% of births resulting from clomiphene (CC) will be twins, and less than 1% of births will be triplets and HOMB. These figures increase to 20% and 8% respectively for births resulting from gonadotropins. For younger patients who are high responders, the incidence of triplet and higher-order pregnancies (HOMP) can be 20%. Nearly all HOMB due to OI with gonadotropins in controlled ovarian hyperstimulation (COH) protocols might have been prevented by use of lower doses of gonadotropins, with very little reduction in the number of patients able to conceive. The majority of women who require OI will be able to become pregnant within 3-6 cycles of single or double follicular development using oral drugs or low-dose gonadotropins, with a 10% chance of twins and less than a 1% chance of HOMB.

Introduction

Use of gonadotropins for ovulation induction (OI) in intrauterine insemination (IUI) cycles increases pregnancy rates per cycle compared to IUI alone or with clomiphene (CC-IUI); however, whether pregnancy rates per couple are increased is less certain. Gonadotropin use for OI may be complicated by multiple pregnancies, particularly triplets and higher orders, and by ovarian hyperstimulation syndrome (OHSS). Their use as first-line treatment should be limited to those women who have hypopituitary or hypothalamic amenorrhea not correctable by other treatment. Gonadotropins should not be used in the treatment of “unexplained infertility” for patients who ovulate, but fail to conceive, until a minimum of three cycles of CC with IUI have been tried first. Gonadotropins should not be used in place of CC because of its anti-estrogen effect on endometrial thickness and cervical mucus before first trying tamoxifen (TMX) 40–60 mg for five days instead of CC. These proscriptions will, if followed, significantly reduce the risk of multiple pregnancy and the risk of OHSS.

The risk of multiple pregnancy is related to the number of preovulatory follicles (more with gonadotropins, fewer with CC and TMX), patient's age and initial cycle of treatment.

Introduction

Intrauterine insemination (IUI) and ovulation induction (OI) are oft en combined in order to increase the effectiveness of infertility treatment. The reason most frequently given for combining OI with IUI to treat male-factor infertility is to maximize the possibility of pregnancy by increasing the number of preovulatory follicles. However, unless the female partner is anovulatory or has luteal deficiency, there is conflicting evidence on whether oral OI drugs do increase pregnancy rates in IUI cycles. On the other hand, there is undeniable evidence that IUI does improve pregnancy rates in many cases when clomiphene citrate (CC) is used to treat ovulation dysfunction or luteal insufficiency. Whether IUI should be used in all OI cycles, or only if there is either a poor postcoital test (PCT) or semen quality below WHO standards, is arguable. At the Fertility Institute of New Orleans only 20% of 3,400 CC pregnancies have required IUI.

The advantages of oral drugs over gonadotropin for OI include a low incidence of multiple pregnancies and ovarian hyperstimulation syndrome (OHSS), low cost, oral administration and less need for cycle monitoring. However, due to its antiestrogenic nature, CC may adversely affect cervical mucus and endometrial receptivity. Tamoxifen (TMX), a structurally related selective estrogen receptor modulator (SERM) that has a weak estrogenic effect on cervical mucus and the endometrium, and letrozole (LET), an aromatase inhibitor, are used “off label” to replace CC.

Action

CC and TMX are competitive antagonists of ovarian estrogen at hypothalamic receptor sites, and exhibit either antiestrogenic activity (CC) or weak estrogenic activity (TMX) at peripheral receptor sites (Fig. 7.1).