Infertility Treatment- Chapter 10:

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Q 10. 1 What are the objectives of infertility treatment?

The objective of treatment for couples with infertility is to achieve a successful pregnancy quickly and safely with the least intervention required whilst recognising the sensitivity of patients and their need to participate in decision making.

Q 10. 1 What are the objectives of infertility treatment?
Q 10. 2 Why have I been advised to take folic acid as part of my infertility treatment?
Q 10. 3 Although my ovaries have eggs in them, my tests show that I am not releasing them (anovulation) and this is causing infertility. How can this be treated?
Q 10. 4 If I take drugs to induce ovulation (ovulation induction) for my infertility, are there any risks?
Q 10. 5 How is ovulation induction treatment for infertility monitored?
Q 10. 6 How does clomiphene citrate work for infertility?
Q 10. 7 How effective is clomiphene in the treatment of infertility?
Q 10. 8 Could I experience any problems whilst taking clomiphene?
Q 10. 9 Is there any advantage in having an injection of HCG to ensure ovulation?
Q 10. 10 How does tamoxifen work?
Q 10. 11 How can hyperprolactinaemia be treated?
Q 10. 12 How does metformin work?
Q 10. 13 How do gonadotrophins work?
Q 10. 14 What are the risks for me if I receive gonadotrophin therapy?
Q 10. 15 What are recombinant gonadotrophins?
Q 10. 16 What is ovarian hyperstimulation syndrome (OHSS)?
Q 10. 17 How is ovarian hyperstimulation syndrome treated?
Q 10. 18 How does electrocautery (ovarian drilling) work for infertility associated with polycystic ovary syndrome (PCOS)?
Q 10. 19 I have been found to have endometriosis. How should this be treated to improve my chance of conceiving?
Q 10. 20 Tests have shown that I have problems with my Fallopian tubes. What can be done about this?
Q 10. 21 I have fibroids. How should these be treated to improve my fertility?
Q 10. 22 My post-coital test has shown that my mucus is stopping the sperm from swimming (mucus hostility). What can be done?
Q 10. 23 When can intrauterine insemination (IUI) improve our chance of achieving a pregnancy?
Q 10. 24 What is in vitro fertilisation (IVF) and embryo transfer (ET).
Q 10. 25 What is intracytoplasmic sperm injection (ICSI)?
Q 10. 26 How do tubal surgery and IVF compare?
Q 10. 27 What are egg donation and egg sharing?
Q 10. 28 What is selective embryo transfer?
Q 10. 29 Investigations have shown no obvious cause for our difficulty achieving a pregnancy. Are there any treatments for our unexplained infertility?
Q 10. 30 We have tried a variety of treatments but we still have not achieved a pregnancy. Why should this be?
Q 10. 31 We are finding the investigation and treatment of our fertility problems to be ever more stressful. Can stress be a cause of infertility?
Q 10. 32 How can we determine which fertility unit is likely to be the best for us?
Q 10. 33 Where can I obtain more information?
Q 10. 34 Could I have some useful Web sites?
Women’s Health – Home Page

Q 10. 2 Why have I been advised to take folic acid supplements?

If a couple have had pregnancy where the baby or foetus had a neural tube defect (spina-bifida type problem) they have an increased risk of a similar problem recurring – about one in a hundred. Controlled trials (Q33.26) have demonstrated that folic acid supplements (4 or 5mg daily) reduces this risk by 75% and it is believed that benefit is likely even if you have never had such a problem. The folic acid is not specifically recommended because of infertility but would be advised for any woman planning to conceive.

References:

Blood folic acid and vitamin B12 in relation to neural tube defects (1996) 10-02-1261

Folic acid prescription and pregnancy (1995) 10-02-2124

Prevention of neural tube defects: Results of the Medical Research Council vitamin study (1991) 10-02-106

Q 10. 3 Although my ovaries have eggs in them, my tests show that I am not releasing them (anovulation). How can we induce ovulation?

With the exception of primary ovarian failure (the menopause), ovulatory disorders can usually be successfully treated. Ovulation induction regimens depend on the underlying cause (Q 9.3).

Sometimes appropriate advice may be all that is required. When weight loss is responsible for secondary amenorrhoea (Q6.7), improved diet leading to correction of your weight may prove to be successful.

The main drugs used to overcome anovulation are clomiphene (Q10.6), tamoxifen (Q10.10), bromocriptine (Q10.11), metformin (Q10.12), and gonadotrophins (Q10.13).

References:

Ovulation induction using s.c. pulsatile gonadotrophin-releasing hormone: Effectiveness of different pulse frequencies (1996) 10-03-1125

Anovulatory and ovulatory infertility: results with simplified management (1982) 10-03-746

Investigation and treatment of amenorrhoea resulting in normal fertility (1979) 10-03-745

Q 10. 4 If I take drugs to induce ovulation (ovulation induction), are there any risks?

There are three concerns associated with drugs used to induce ovulation:

• They are associated with a greater chance of multiple pregnancy. The general rate of twins in the population is one in every eighty deliveries but with clomiphene it is one in twenty or a four-fold increase. Higher order multiple pregnancies (e.g. triplets and quads) can occur with clomiphene but this is rare. Injections of gonadotrophins are more likely than clomiphene to result in multiple pregnancy.

• Occasionally ovulation induction can lead to ovarian hypersensitivity syndrome (Q10.16).

• Finally, there has been concern that ovulation induction treatments may increase the chance of ovarian cancer although this risk has probably been overstated (Q10.8).

References:

Fertility drugs and the risk of breast and ovarian cancers: Results of a long-term follow-up study. (1999) 10-04- 2666

The risk of ovarian cancer after treatment for infertility (1996) 10-04-1253

Ovarian stimulation and ovarian tumours: a critical reappraisal (1995) 10-04-1216

Ovarian tumors in a cohort of infertile women (1994) 10-04-1090

Characteristics relating to ovarian cancer risk: Collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women (1992) 10-04-1095

Q 10. 5 How is ovulation induction treatment monitored?

Monitoring may be required to confirm that ovulation is occurring and to ensure that too many follicles are not developing. Blood tests for progesterone levels around the twenty-first day of the cycle provide an indication of ovulation (Q9.17). Ultrasound monitoring of follicular development is helpful with tablet treatment (clomiphene and tamoxifen) and is really essential with gonadotrophins.

References:

The role of infertility nurses in ovulation induction programmes (2001) 10-05-3369

Is it possible to run a successful ovulation induction program based solely on ultrasound monitoring? The importance of endometrial measurements (1991) 10-05-695

Q 10. 6 How does clomiphene citrate (Clomid) work?

Clomiphene citrate, although not a steroid (Q2.9), has a biochemical configuration similar to that of oestrogens. It modifies hypothalamic and pituitary activity by binding to oestrogen receptor sites (Q2.8). The negative feedback effect of oestrogens from the ovaries (Figure 10.1) is blocked and the hypothalamus and pituitary gland assume a falsely low reading of oestrogen levels. As a result, GnRH activity and also FSH and LH output from the pituitary are increased and this increases the drive stimulating the ovarian follicles and egg release.

References:

Cycle abnormalities in infertile women with regular menstrual cycles: Effects of clomiphene citrate treatment (1994) 10-06-372

Q 10. 7 How effective is clomiphene?

Ovulation rates can be in the region of ninety per cent but pregnancy rates do not exceed sixty per cent. Clomiphene therapy is traditionally started with 50mg daily for five days. We generally commence on the second day of the cycle although there is probably no clinical advantage arising from the exact start day. Some commence the clomiphene on the fifth day.

References:

Is treatment of long-term and consecutive use of clomiphene citrate effective in anovulatory patients? Results of multi-centric retrospective studies (1994) 10-07-1454

A clomiphene citrate and tamoxifen citrate combination therapy: a novel therapy for ovulation induction (1993) 10-07-683

The effect of therapy initiation day on clomiphene citrate therapy (1989) 10-07-687

Ovulation and pregnancy rates with clomiphene citrate (1978) 10-07-686

Q 10. 8 Could I experience any problems whilst taking clomiphene?

There is a slightly increased chance of multiple pregnancy and ovarian hyperstimulation syndrome (Q10.16). Other side effects of clomiphene therapy include hot flushes and headaches but these are not usually severe enough to discontinue treatment and may be less troublesome with time.

The majority of pregnancies occur in the first few treatment cycles. Some find that simple monitoring with basal temperature alone is as good as urinary LH monitoring and ultrasound for the first few clomiphene cycles but we prefer checking progesterone levels on the twenty-first day of the cycle. If there is no success with 50mg, the dose can slowly be increased in 50mg increments up to 200mg daily for five days.

Although attention has been drawn to the anti-oestrogenic activity of clomiphene, there is probably no substance in the suggestion that the cervical mucus is adversely affected. There would appear to be no increased risk of congenital abnormality (Q3.3) in pregnancy after clomiphene ovulation induction. Early pregnancy loss and ectopic pregnancy rates are not significantly increased in association with clomiphene induced ovulation.

There continues to be debate on the question of a relationship between the use of clomiphene and later development of ovarian cancer. The debate arose in 1994 when an analysis of 3,837 women previously investigated for infertility in Seattle between 1974 and 1985 was reported. Invasive or borderline malignant tumours of the ovaries had subsequently developed in 11 women whereas statistically four or five would have been expected. Nine of the women developing ovarian malignancy had taken clomiphene and five of these nine had taken the drug for twelve months or more. Treatment with clomiphene for less than a year was not associated with increased risk. The consensus is that the risk has probably been overstated. If it is clinically felt to be in your interests for you to continue with clomiphene this is medically acceptable provided that you have been given the current information.

References:

Treatment of chronic anovulation resistant to clomiphene citrate (CC) by using oral contraceptive ovarian suppression followed by repeat CC treatment. (1999) 10-08-2585

Ovulation induction, infertility, and ovarian cancer risk (1996 ) 10-08-1424

Q 10. 9 Is there any advantage in having an injection of HCG to ensure ovulation?

Human gonadotrophic hormone (HCG), which is produced by the early pregnancy tissues, keeps the corpus luteum functioning (Q2.13). HCG is almost identical chemically to LH. It is a surge of LH that normally results in ovulation (Figure 2.3). When there is evidence of follicular development with clomiphene but ovulation or pregnancy do not occur, HCG administration can increase the chance of conception. The HCG should be given when the leading follicle reaches approximately 18mm diameter as visualised by ultrasound.

References:

Intrauterine insemination: Effect of the temporal relationship between the luteinizing hormone surge, human chorionic gonadotrophin administration and insemination on pregnancy rates (1997) 10-09-2038

Human menopausal gonadotropin and the risk of epithelial ovarian cancer (1996) 10-09-1100

Time interval from human chorionic gonadotrophin (HCG) injection to follicular rupture (1995) 10-09-1172

Ultrasound timing of human chorionic gonadotropin administration in clomiphene-stimulated cycle (1982) 10-09-696

Therapeutic induction of ovulation: towards the replacement of hCG with LH (1994) 10-09-693

Evaluation of whether using hCG to stimulate oocyte release helps or decreases pregnancy rates following intrauterine insemination (1994 ) 10-09-692

Evaluation of clomiphene citrate and human chorionic gonadotropin treatment: a prospective, randomized, crossover study during intrauterine insemination cycles (1994) 10-09-691

Q 10. 10 How does tamoxifen work?

Tamoxifen is an anti-oestrogen and it is generally considered to increase fertility rates in a similar way to clomiphene. In contrast to clomiphene, however, tamoxifen does not increase follicular phase FSH and LH levels, although there is an increase in oestradiol levels and luteal phase progesterone. It has, therefore, been postulated that tamoxifen improves follicular development by direct action on the ovary rather than through the hypothalamic-pituitary axis (Q2.14). We usually start with 20mg daily from the second to the sixth day and build up to a maximum of 80mg. When used for short periods, tamoxifen does not appear to be associated with any increased risk of either ovarian or endometrial malignancy. Early studies indicated similar success rates between tamoxifen and clomiphene. In one series of 66 anovulatory patients, both drugs achieved pregnancy rates of 80% within nine months. When clomiphene fails to achieve ovulation or pregnancy, tamoxifen may prove to be effective and vice versa. Some authorities have recommended tamoxifen as their first choice for women with polycystic ovary syndrome (PCOS). The argument has been that PCOS is associated with relatively high levels of LH and this seems to reduce the chance of conception and increase the chance of miscarriage. Unlike clomiphene, tamoxifen does not further increase LH levels. Metformin may supersede tamoxifen and clomiphene as the first choice agent in PCOS (Q10.12).

References:

Tamoxifen: an alternative approach in clomiphene resistant polycystic ovarian syndrome patients (1993) 10-10-478

Effects of the anti-oestrogens, clomiphene and tamoxifen, on the cervical factor in female infertility (1984) 10-10-469

Treatment of infertile women with a deficient postcoital test with two antiestrogens: clomiphene and tamoxifen (1984) 10-10-468

Tamoxifen treatment in women with failure of clomiphene citrate therapy (1989) 10-10-474

Antiestrogens as treatment of female and male infertilities (1987) 10-10-475

Endocrine profiles in tamoxifen-induced conception cycles (1984) 10-10-473

Luteotropic effects of tamoxifen in infertile women (1984) 10-10-472

Action of tamoxifen on folliculogenesis in the menstrual cycle of infertile patients (1983) 10-10-704

Comparison between tamoxifen and clomiphene for induction of ovulation (1982) 10-10-471

Q 10. 11 How can hyperprolactinaemia be treated?

Since 1976, bromocriptine, which inhibits prolactin secretion by the pituitary, has been the drug of choice (Q6.21) and ovulation rates of 90 per cent and pregnancy rates of 75 per cent have been reported. There would not appear to be any adverse effects on pregnancy outcome following cessation of bromocriptine or even if bromocriptine is continued throughout pregnancy; we advise that treatment be stopped as soon as pregnancy is confirmed.

The standard dose of bromocriptine is 2.5mg twice daily although much higher doses are sometimes required to achieve normal prolactin levels. Side effects frequently occur and include headache, nausea and diarrhoea. These problems can be reduced by prescribing a gradually escalating regime starting with half a tablet at night and increasing at four day intervals. Occasionally the vaginal route of administration proves to be better tolerated.

Recently there have been some new agents that may prove to be better tolerated than bromocriptine. Cabergoline may become the drug of choice although it is currently relatively expensive.

References:

The safety of bromocriptine in hyperprolactinaemic female infertility: a literature review (1986) 10-11-759

Q 10. 12 How does metformin work for infertility associated with PCOS (Polycystic Ovary Syndrome)?

Metformin has recently become recognised as potentially beneficial for women with infertility and PCOS (Q7.14). This syndrome appears to be related to insulin resistance, which is reversed by the metformin. Early reports are encouraging. As metformin works by reversing the underlying disease process rather than specifically inducing ovulation, it seems likely that it will not be associated with the risks of ovulation induction (Q10.8).

A twenty-nine year old lady had been found to have PCOS at the age of 16. Her periods had always been infrequent and she had never used contraception. She conceived six weeks after commencing metformin.

References:

Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. (1999) 10-12-3229

Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. (1999) 10-12-2982

Q 10. 13 How do gonadotrophins work?

The gonadotrophins (FSH and LH) are released from the pituitary and they stimulate the ovaries (Figure 10.1). Gonadotrophins have become commercially available using extraction techniques on urine from menopausal women (HMG) who have high levels of gonadotrophins. The objective of gonadotrophin therapy is to produce mature follicles, which can be released by injection of HCG.

For “low-tech” treatment the objective is to stimulate maturation preferably of one follicle but with a maximum of three follicles. Patients who fail to ovulate or conceive with clomiphene or tamoxifen are candidates for gonadotrophin therapy. Tubal patency, normal prolactin levels and satisfactory semen analysis are essential pre-requisites. Patients with hypergonadotrophic hypogonadism (menopausal gonadotrophin levels) do not respond to gonadotrophin therapy. There have been a variety of regimens for the administration of gonadotrophins. The fixed regimen involves a predetermined dose administered in a single intra-muscular injection on three alternate days e.g. Days 1, 3 and 5 of the menstrual cycle and HCG is given three days later if the oestrogen response is in the accepted range.

In the variable regimen, gonadotrophins tended to be administered daily, the dose being adjusted according to plasma or urinary oestradiol results. In the early days of gonadotrophin therapy, the only investigation for monitoring ovarian response was oestrogen assay of urine or blood. Ultrasound tracking of follicular development (Q4.9), initially transabdominally and more recently by the transvaginal route, has provided a valuable addition for the monitoring of gonadotrophin therapy.

References:

Clinical experience with recombinant follicle-stimulating hormone (FSH) and urinary FSH: A retrospective case- controlled analysis (2001) 10-13-3361

Q 10. 14 What are the risks for me if I receive gonadotrophin therapy?

The risks of gonadotrophin therapy are:

• multiple pregnancy (twins, triplets etc.): rates are higher with gonadotrophins than clomiphene.

• ovarian hyperstimulation syndrome (Q10.16) is more commonly associated with polycystic ovary syndrome and accordingly for these women, the quantity of gonadotrophin administered should be reduced. Some units continue to monitor oestrogen levels in addition to ultrasound but it has been shown that ultrasound alone can be used safely and efficiently.

As with clomiphene (Q10.8), there is concern that gonadotrophin therapy may be associated with an increased risk of ovarian cancer although the latest data does not support the earlier anxieties.

References:

Treatment for infertility and risk of invasive epithelial ovarian cancer (1997) 10-14-2037

The feasibility of assessing women’s perceptions of the risks and benefits of fertility drug therapy in relation to ovarian cancer risk (1997) 10-14-1804

Risk factors in breast carcinoma (1991) 10-14-645

Low multiple pregnancy rate in combined clomiphene citrate – Human menopausal gonadotropin treatment for ovulation induction or enhancement (1989) 10-14-690

Q 10. 15 What are recombinant gonadotrophins?

The most recent advance in gonadotrophin production involves recombinant DNA technology. The DNA code (Q32.1) for FSH has been defined and can be inserted into mammalian cells, which then produce the FSH. The resultant recombinant human FSH has become commercially available (Gonal-F – Serono; Puregon – Organon).

References:

Recombinant technique and gonadotropins production: New era in reproductive medicine (1996) 10-15-1525

Q 10. 16 What is ovarian hyperstimulation syndrome (OHSS)?

This is a possible complication of ovulation induction. In its mild form it is of little significance but in its severe form it is potentially dangerous.

Mild OHSS is characterised by some abdominal distension and discomfort and there may be sickness and diarrhoea. The ovaries may enlarge up to 12 cms. In moderate OHSS there may be some excess of fluid in the abdomen. Severe OHSS is characterised by free fluid in the abdomen that can be detected clinically, even without ultrasound. Occasionally there may be changes in the blood. It is believed that there are about 100,000 cycles of assisted conception annually around the world and about 100 cases of severe OHSS. The risk of severe OHSS is therefore one in a thousand IVF treatments.

References:

The ovarian hyperstimulation syndrome. (2000) 10-16-3084

Obstetric outcome of in vitro fertilized pregnancies complicated by severe ovarian hyperstimulation syndrome: A multicenter study. (1998) 10-16- 2497

The pathophysiology of ovarian hyperstimulation syndrome – Views and ideas (1997) 10-16-1853

Severe ovarian hyperstimulation syndrome in assisted reproductive technology: Definition of high risk groups (1991) 10-16-235

Q 10. 17 How is ovarian hyperstimulation syndrome treated?

The first objective is to prevent OHSS from developing. During treatment cycles, if there is evidence that there is a significant risk that OHSS could occur, the cycle may be abandoned or treatment dosage reduced. When severe OHSS develops, admission to hospital and correction of changes in the blood are required.

References:

Intravenous albumin for preventing severe ovarian hyperstimulation syndrome: a Cochrane review. (2002) 3556

High pregnancy rates and successful prevention of severe ovarian hyperstimulation syndrome by ‘prolonged coasting’ of very hyperstimulated patients: A multicentre study. (1999) 10-17-2598

A novel approach to the treatment of ascites associated with ovarian hyperstimulation syndrome. (1997) 10-17-3137

Does intravenous administration of human albumin prevent severe ovarian hyperstimulation syndrome? (1996) 10-17-1520

‘Prolonged coasting’: An effective method for preventing severe ovarian hyperstimulation syndrome in patients undergoing in-vitro fertilization (1995) 10-17-1170

Decreased incidence of severe ovarian hyperstimulation syndrome in high risk in-vitro fertilization patients receiving intravenous albumin: A prospective study (1995) 10-17-1001

Day care management of severe ovarian hyperstimulation syndrome avoids hospitalization and morbidity (1994) 10-17-390

The use of intravenous albumin in patients at high risk for severe ovarian hyperstimulation syndrome (1993) 10-17-291

Q 10. 18 How does electrocautery (ovarian drilling) work for infertility associated with polycystic ovary syndrome (PCOS)?

For more than sixty years, we have known that women with PCOS are prone to infrequent periods and infertility. When a section of the ovaries was removed for microscopic examination, many women with PCOS became pregnant. The exact mode of action has not yet been fully determined. Those with expertise in minimally invasive surgery have shown that small holes can be drilled into polycystic ovaries at the time of laparoscopy with clinical benefit. Only time will determine whether metformin (Q10.12) or ovarian drilling will prove to be more effective but it would seem prudent to try a medical treatment first.

Bibliography:–

A randomized controlled trial of laparoscopic ovarian diathermy versus gonadotropin therapy for women with clomiphene citrate-resistant polycystic ovary syndrome. (2002) 3554

Q 10. 19 I have been found to have endometriosis. How should this be treated to improve my chance of conceiving?

Mild endometriosis does not seem to be a factor in infertility and randomised trials (Q33.26) comparing medical treatments (Q23.21) including danazol, gestrinone, medroxyprogesterone acetate and GnRH analogues with controls have shown no advantage in terms of pregnancy rates.

When there is severe endometriosis, pregnancy rates of 50% have been achieved following restoration of normal anatomy at laparotomy and similar success rates may be possible with minimally-invasive surgery.

Q 10. 20 Tests have shown that I have problems with my Fallopian tubes. What can be done about this?

The success rates following tubal surgery will depend on the severity of the disease. Careful pre-operative assessment, including semen analysis and often hysterosalpingography and laparoscopy, is required.

The commonest site of tubal damage is at the fimbrial end (opening near the ovaries – Figure 9.1), with birth rates after surgery in the order of 25 per cent. Surgery for proximal tubal occlusion (the blockage is close to the uterus) is more successful, with live birth rates of 50% and ectopic rates of 10%. Just over a half of intrauterine pregnancies following tubal surgery may occur more than one year after surgery. Reversal of sterilisation, with removal of clips and re-anastomosis (reconnection), carries a relatively high success rate of up to 80%.

Tubal microsurgery involves the use of magnification as well as the adoption of a set of techniques including the use of special instruments, minimal handling of the Fallopian tubes and fine non-reactive suture material. There have been no controlled trials to prove conclusively an advantage over conventional surgical techniques but several surgical teams have reported improved success rates. It is technically possible to transplant Fallopian tubes and large numbers of these organs would undoubtedly be donated by women undergoing sterilisation or hysterectomy (hysterectomy) . Research interest in this area seems to have diminished following the development of IVF (Q10.24).

References:

Laparoscopic management of hydrosalpinges before in vitro fertilization-embryo transfer: Salpingectomy versus proximal tubal occlusion (2001) 10-20-3254

Cochrane review: Post-operative procedures for improving fertility following pelvic reproductive surgery. (2000) 10-20-3147

Pharmacological adjuvants during infertility surgery: A systematic review of evidence derived from randomized controlled trials. (1999) 10-20-2973

Ultrasound-guided aspiration of hydrosalpinges is associated with improved pregnancy and implantation rates after in-vitro fertilization cycles. (1998) 10-20-3101

In-vitro fertilization outcome in women with hydrosalpinx (1996) 10-20-1247

Q 10. 21 I have fibroids. How should these be treated to improve my fertility?

Fibroids become more common in the later years of reproductive life (Q23.15). The relationship between fibroids and infertility has been the subject of debate. Implantation and pregnancy rates have been found to be reduced only when the fibroids are distorting the endometrial cavity (submucous fibroids). Until recently, the only treatment was myomectomy at laparotomy. Developments with minimally invasive surgery and in particular transcervical hysteroscopy (Figure 24.2) allow resection of submucous fibroids. Controlled trials are required to establish the benefits.

References:

Myomectomy: A retrospective study to examine reproductive performance before and after surgery. (1999) 10-21-2733

Abdominal myomectomy for infertility: A comprehensive review. (1998) 10-21-3127

Q 10. 22 My post-coital test has shown that my mucus is stopping the sperm from swimming (mucus hostility). What can be done?

Hostile cervical mucus may be more acidic than normal. Treatment with sodium bicarbonate (a level teaspoonful dissolved in half a pint of lukewarm water), and 40ml of the solution introduced into the vagina with a syringe about two hours before coitus, can significantly improve pregnancy rates. Oestrogens (e.g. Premarin 0.625) have been administered in the preovulatory phase from day 9 to day 13 of the menstrual cycle for cervical mucus factor infertility. Mucus hostility may be associated with antibodies being produced against sperm. At one time, sperm antibody tests were arranged and steroids administered if the results were positive. Steroid treatment has some dangers and these days artificial insemination (Q10.23) or IVF seem more appropriate.

References:

Exogenous estrogen therapy for treatment of clomiphene citrate-induced cervical mucus abnormalities: Is it effective? (1990) 10-21-700

Q 10. 23 When can intrauterine insemination (IUI) improve our chance of achieving a pregnancy?

Intrauterine insemination (IUI – artificial insemination – AI) of your partner’s sperm has a place when there is:-

• known to be a coital problem, either elucidated from the history or perhaps from repeated observation of absence of sperm on post-coital testing.

• mildly reduced male fertility, as recognised from semen analysis. Even when there is moderate male subfertility, treatment using ovulation induction and IUI would seem to be a valuable initial treatment before contemplating more expensive and invasive assisted reproductive techniques. Severe male factor infertility does not usually respond to IUI.

• cervical hostility demonstrated by post-coital testing or mucus penetration tests.

• unexplained infertility.

At one time, untreated semen was used but adverse reactions sometimes occurred. These days, sperm for insemination are prepared by washing or swim-up to improve success rates and reduce possible complications. The swim-up preparation involves washing the sperm with culture medium, and, after centrifugation (controlled rapid spinning), the supernatant (fluid) is removed. The pellet of sperm is covered by 0.5ml of culture media. In the swim-up preparation, the sperm in the pellet are incubated at body temperature for 30-60 minutes. The supernatant subsequently carries a relatively high concentration of motile sperm and this is used for the insemination procedure. A variety of swim-up techniques and media such as Percoll have been used in an attempt to improve success rates.

Clearly artificial insemination should be undertaken around the time of ovulation. The relationship between the day of insemination in relation to the last day of hypothermia (low temperature) on the basal temperature chart and conception rates in a donor insemination protocol has been studied. The over-all conception rate was 12% and the best results were obtained for insemination 3 days (20%) and 1 day (21%) before the last day preceding the temperature rise that is typical following egg –release. LH predictor tests can be used to indicate the fertile phase for a woman with irregular cycles, perhaps increasing the success rate. Success rates with artificial insemination depends on the age of the female partner and the total motile sperm count.

Artificial insemination with donor sperm (AID) has been the most successful treatment for male factor infertility although, not withstanding economic considerations, more modern treatments with IVF and ICSI (Q10.25) have an increasing role to play. Success rates in donor insemination programmes of 70% over six cycles have been reported. Frozen samples are now recommended to allow adequate testing of donors for HIV although fresh donor samples have achieved pregnancy rates of 19% per cycle compared to frozen samples giving 5 –10 % per cycle.

References:

Effect of the total motile sperm count on the efficacy and cost-effectiveness of intrauterine insemination and in vitro fertilization (2001) 10-23-3294

A comparison of intrauterine versus intracervical insemination in fertile single women (2001) 10-23-3291

Prospective, randomized, crossover study to evaluate the benefit of human chorionic gonadotropin-timed versus urinary luteinizing hormone-timed intrauterine inseminations in clomiphene citrate-stimulated treatment cycles. (1999) 10-23-2834

Single versus double insemination: A retrospective audit of pregnancy rates with two treatment protocols in donor insemization (1997) 10-23-2156

Treatment of male infertility due to sperm surface antibodies: IUI or IVF? (1997) 10-23-1855

Intrauterine insemination: Evaluation of the results according to the woman’s age, sperm quality, total sperm count per insemination and life table analysis (1996) 10-23-1278

Time interval from human chorionic gonadotrophin (HCG) injection to follicular rupture. (1995) 10-23-2612

A comparison of intrauterine insemination in superovulated cycles to intercourse in couples where the male is receiving steroids for the treatment of autoimmune infertility (1995) 10-23-1452

Cumulative conception rate following intrauterine artificial insemination with husband’s spermatozoa: Influence of husband’s age (1995) 10-23-654

Time schedules of intrauterine insemination after urinary luteinizing hormone surge detection and pregnancy results (1994) 10-23-1140

Intrauterine insemination as treatment for antisperm antibodies in the female (1988-673

The treatment of infertility by the high intrauterine insemination of husband’s washed spermatozoa (1988-672

Superovulation with intrauterine insemination in the treatment of infertility: a possible alternative to gamete intrafallopian transfer and in vitro fertilization (1987-80

Q 10. 24 What is in vitro fertilisation (IVF) and embryo transfer (ET).

In vitro fertilisation means that the eggs are fertilised outside the body. It involves the collection of eggs from the ovaries. Each egg is placed in a special dish together with sperm to facilitate fertilisation and early development of embryos. Eggs, sperm and embryos are very sensitive and they are cared for by embryologists who ensure that they are nurtured in the most perfect environment within special incubators. About two days after egg collection, embryos (Figure 10.2) are transferred into the uterus.

In vitro fertilisation was initially developed for women who had severe tubal disease or who had their Fallopian tubes removed but this treatment has also proved successful for unexplained infertility and male factor infertility. A typical IVF treatment cycle is outlined in Figure 10.3. Originally, eggs were collected laparoscopically (Q23.24) but we now collect the eggs by ultrasound guidance usually through the vagina.

The IVF pioneers collected just one egg immediately before ovulation but now we use gonadotrophin injections to increase the number of eggs available for collection (superovulation). Natural gonadotrophin release from the pituitary is suppressed (down regulation) by GnRH (Q33.16) to prevent ovulation before the eggs are collected. Ultrasound and hormone assays are required to optimise follicular development. In the UK a maximum of three embryos can be transferred into the uterine cavity usually two days after egg collection.

IVF is a complicated treatment requiring dedication from highly trained clinical and embryology staff. In the UK, clinics offering IVF require a licence from a government appointed body –The Human Embryology and Fertilisation Authority who monitor the work of IVF units. IVF treatments are highly confidential.

References:

Women’s experience of IVF: A follow-up study (2001) 10-24-3411

Cumulative conception and live birth rates in natural (unstimulated) IVF cycles (2001) 10-24-3410

Embryo score is a better predictor of pregnancy than the number of transferred embryos or female age (2001) 10-24-3249

Aims of the HFEA: Past and future (1999) 10-24-2972

Crinone 8% vaginal progesterone gel results in lower embryonic implantation efficiency after in vitro fertilization-embryo transfer (1999) 10-24-2954

The influence of bacterial vaginosis on in-vitro fertilization and embryo implantation during assisted reproduction treatment. (1999) 10-24-2774

Is blastocyst transfer useful as an alternative treatment for patients with multiple in vitro fertilization failures? (1999) 10-24-2755

Low-dose aspirin treatment improves ovarian responsiveness, uterine and ovarian blood flow velocity, implantation, and pregnancy rates in patients undergoing in vitro fertilization: A prospective, randomized, double-blind placebo-controlled assay. (1999) 10-24-2665

Use of Crinone vaginal progesterone gel for luteal support in in vitro fertilization cycles (1999) 10-24-2953

Microbial flora of the cervix assessed at the time of embryo transfer adversely affects in vitro fertilization outcome. (1998) 10-24-2476

Triplets and embryo transfer policy (1997) 10-24-2065

A triplet pregnancy after in vitro fertilization is a procedure-related complication that should be prevented by replacement of two embryos only (1997) 10-24-2023

The embryo versus endometrium controversy revisited as it relates topredicting pregnancy outcome in in-vitro fertilization-embryo transfer cycles (1997) 10-24-1864

Luteal support after in-vitro fertilization: Crinone 8%, a sustained release vaginal progesterone gel, versus Utrogestan, an oral micronized progesterone (1996) 10-24-1596

Q 10. 25 What is intracytoplasmic sperm injection (ICSI)?

If there is severe male factor infertility or previous IVF with failure to fertilise, one sperm can be injected into each egg – intracytoplasmic sperm injection (ICSI) to increase the chance of success (Figure 10.4).

References:

Should ICSI be the treatment of choice for all cases of in-vitro conception? No, not in light of the scientific data. (10-25-3526)

Chromosomal findings in 150 couples referred for genetic counselling prior to intracytoplasmic sperm injection (1997) 10-25-1850

Preferences for intracytoplasmic sperm injection versus donor insemination in severe male factor infertility: A preliminary report. (1996) 10-25-1650

Q 10. 26 How do tubal surgery and IVF compare?

Information about success rates is essential for couples to make informed decisions. In vitro fertilization (IVF) provides an alternative to tubal surgery. For mild tubal disease and previous sterilisation, tubal surgery is probably the treatment of first choice. With severe tubal disease, IVF carries the better success rate. For intermediate disease, the optimum method in terms of success is less certain. IVF is becoming increasingly successful (Figure 10.5) and appropriately more popular (Figure 10.6).

The merits of tubal surgery and assisted reproduction (Assisted Reproductive Technology – ART) need careful comparison. In-vitro fertilisation is becoming more readily available with a corresponding reduction in the use of tubal surgery.

IVF is associated with a higher incidence of multiple pregnancy. Perinatal mortality rates following assisted conception procedures are treble that of spontaneous conception although most of the increase is related to multiple pregnancy. There is a five-fold increase in perinatal mortality (stillbirths and first week losses) with triplets compared with singletons. The predicted costs associated with delivery of each baby for a singleton pregnancy in the USA in 1991 was $9,845, for a twin pregnancy $18,974 and for triplets $36,588. Between 1986 and 1991, assisted reproduction techniques were found to be responsible for 35% of twins and 77% of higher order pregnancies.

In the NHS only about 25% of purchasing authorities are currently supporting IVF treatment and the number is falling. There can be little doubt, that from a purely economic point of view, a greater number of pregnancies could be achieved with a given amount of funding using low tech treatments. Many couples would prefer tubal surgery in the first instance and the opportunity to conceive naturally, only resorting to IVF if this fails.

References:

Reversal of sterilisation vs. IVF: A cost-benefit analysis (1997) 10-26-1728

Tubal surgery versus assisted reproduction: assessing their role in infertility therapy (1995) 10-26-662

Q 10. 27 What are egg donation and egg sharing?

Some women are unable to produce healthy eggs either because they have reached their menopause early, they are approaching their menopause (Figure 10.7) or because their eggs carry abnormal genes. The only realistic chance of a successful pregnancy in these circumstances is if another woman donates some of her eggs. There are some remarkable women who, for altruistic reasons, come forward voluntarily and go through the regimen for IVF egg collection and donation. Egg donors should usually be aged 35 years or less.

The demand for egg donation greatly exceeds supplies. There are many women who have healthy eggs and need IVF but for economic reasons IVF is beyond them. The combined requirements of funding for IVF for the less privileged and of others for egg donors has led to the development of eggs sharing. If a woman requiring egg donation will fund the two treatments, she may receive perhaps half the eggs provided by the woman who has quality eggs but cannot afford the treatment.

References:

Counselling couples and donors for oocyte donation: The decision to use either known or anonymous oocytes. (2000) 10-27-3012

Crinone 8% (90 mg)* given once daily for progesterone replacement therapy in donor egg cycles. (1999) 10-27-2997

Gamete donation: Ethical implications for donors (1999) 10-27-2969

Low-dose aspirin for oocyte donation recipients with a thin endometrium: Prospective, randomized study (1997) 10-27-2058

Some psychological aspects of oocyte donation from known donors on altruistic basis (1997) 10-27-2011

Cumulative conception and live birth rates after oocyte donation: Implications regarding endometrial receptivity (1997) 10-27-1868

Age of the uterus does not affect pregnancy or implantation rates; a study of egg donation in women of different ages sharing oocytes from the same donor (1997) 10-27-1867

What are the effects of anonymity and secrecy on the welfare of the child in gamete donation? (1997) 10-27-1820

Oocyte donation to women of advanced reproductive age: Pregnancy results and obstetrical outcomes in patients 45 years and older (1996) 10-27-1651

Oocyte donation program: Pregnancy and implantation rates in women of different ages sharing oocytes from single donor (1996) 10-27-1104

Improvement of pregnancy rates with oocyte donation in older recipients with the addition of progesterone vaginal suppositories (1993) 10-27-331

Q 10. 28 What is selective embryo transfer?

Selective embryo transfer is becoming an option for couples at risk of transmitting an inherited disorder. The embryos are produced by standard IVF techniques. One or two cells are removed (embryo biopsy) from the 6-10 cell embryo and evaluated for the disorder. Only embryos shown to be free of the disorder are transferred into the uterus. Although 25% of the early embryonic cells are removed, the remaining cells have been shown to survive and produce perfectly healthy babies.

The technological advances in IVF such as selective embryo transfer open up potentially serious ethical issues. It is technically possible, for example, to determine the sex of the embryos, which leads to sex selection. A couple may have several boys but no girls and some seek IVF with sex selection. Technically, IVF with embryo selection according to sex is possible although this is a difficult ethical issue that has already engendered debate in the medical literature. Most of us working with infertility feel unhappy about the concept of selection for non-medical reasons but society will have to address this option in time. In the UK it is illegal to undertake sex selection.

References:

Clinical application of preimplantation genetic diagnosis (2001) 10-28-3370

New advances in sex preselection (1996) 10-28-1465

Obstetric outcome of pregnancies resulting from embryos biopsied for pre-implantation diagnosis of inherited disease (1996) 10-28-1399

Pituitary down-regulation prior to in-vitro fertilization and embryo transfer: A comparison between a single dose of Zoladex depot and multiple daily doses of Suprefact (1995) 10-28-653

Q 10. 29 Investigations have shown no obvious cause for our difficulty achieving a pregnancy. Are there any treatments for our unexplained infertility?

It may, at first, seem disappointing that your tests have not come up with an explanation but in terms of a successful outcome, you are more likely to achieve a pregnancy either with or without treatment than if there were evidence of severe male factor problems or tubal disease. In a summary of the available evidence, it was found that clomiphene, IUI, and HMG each double the chance of conception compared to no treatment (Figure 10.8).

In vitro fertilisation and embryo transfer were originally developed for infertile women who had no Fallopian tubes or who had tubes that were irreversibly damaged. IVF and GIFT (gamete intra Fallopian transfer – eggs and sperm are introduced into the Fallopian Tubes) have found places for other causes of infertility including male factor and unexplained infertility. IVF and GIFT include superovulation (increase in the number of oocytes available for fertilisation), and increasing the number of spermatozoa directly available for each oocyte. For women with no evidence of gross tubal disease, superovulation (gonadotrophin injections) and intrauterine insemination could provide some of the advantages of IVF or GIFT but with less invasive procedures and at lower cost.

Some authorities have recommended that IUI and gonadotrophin injections should be offered to couples with unexplained infertility before submitting them to IVF. A successful outcome is more likely with four courses of this combination than one course of IVF and this low-tech approach is also more cost-effective. Patients with unexplained infertility, who fail to conceive with IUI and superovulation, prove to have a higher incidence of fertilisation failure when they are treated by IVF than patients with tubal factor infertility.

References:

Clomiphene citrate for unexplained subfertility in women (Cochrane Review) 10-29-cochrane

Controlled ovarian hyperstimulation and intrauterine insemination for treatment of unexplained infertility should be limited to a maximum of three trials (2001) 10-29-3258

The clinical efficacy of low-dose step-up follicle stimulating hormone administration for treatment of unexplained infertility. (1999) 10-29-2600

Efficacy of treatment for unexplained infertility (1998) 10-29-2212

The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: A meta-analysis (1997) 10-29-1967

Cost-effectiveness of infertility treatments: A cohort study (1997) 10-29-1794

Clomiphene citrate with intrauterine insemination: Is it effective therapy in women above the age of 35 years? (1996) 10-29-1910

Ovulation induction combined with intrauterine insemination in women 40 years of age and older: Is it worthwhile? (1996) 10-29-1348

Randomized comparison of ovulation induction with and without intrauterine insemination in the treatment of unexplained infertility (1995) 10-29-1173

Ovulation induction with gonadotropins as sole treatment in infertile couples with open tubes: a randomised prospective comparison between intrauterine insemination and timed vaginal intercourse (1995) 10-29-956

Ovulation induction with gonadotropins and intrauterine insemination compared with in vitro fertilization and no therapy: A prospective, nonrandomized, cohort study and meta-analysis (1994) 10-29-933

Unexplained infertility (1993) 10-29-831

Superovulation with or without intrauterine insemination for the treatment of infertility (1992) 10-29-1124

The effects of clomiphene citrate upon ovulation and endocrinology when administered to patients with unexplained infertility (1991) 10-29-967

Unexplained infertility–the value of Pergonal superovulation combined with intrauterine insemination (1988) 10-29-671

Unexplained infertility: a review. [Review] 58 refs 10-29-2316

Q 10. 30 We have tried a variety of treatments but we still have not achieved a pregnancy. Why should this be?

Although there have been tremendous advances in the treatment of infertility, it is a matter of frustration for all concerned that a successful outcome cannot be guaranteed. Sometimes with IVF, fertilisation failure may occur and this could explain for the couple concerned why other treatments have been unsuccessful. The majority of human embryos are lost as a result of implantation failure and any treatment that may reduce this problem would be a major advance in infertility treatment. Low dose aspirin (75 mg daily) improves pregnancy rates in patients with increased antiphospholipid antibody (Q12.17).

It may be difficult to know how long to continue with your infertility treatment. Sometimes a counsellor may provide assistance. It can be particularly difficult if one partner is keen to continue and the other is not. There are times in life when it is helpful to have a plan. You may, for example, decide that you will continue for another six months or a year and then stop. One of the difficulties for you will be that inevitably, with current rates of progress, you may live in hope that a new treatment will prove effective. The medical profession never gives up and is always seeking to improve. Rest assured that however busy your carers may be, they will always have your best interests at heart and they will share with you in any success as well as failures.

References:

Does previous salpingectomy improve implantation and pregnancy rates in patients with severe tubal factor infertility who are undergoing in vitro fertilization? A pilot prospective randomized study (1998) 10-30-2200

Laboratory evaluation of women experiencing reproductive failure (1996) 10-30-1810

Autoimmune disorders: Another possible cause for in-vitro fertilization and embryo transfer failure (1995) 10-30-1811

An endometrial factor in unexplained infertility (1990) 10-30-29

Reduced in-vitro fertilization of human oocytes from patients with raised basal luteinizing hormone levels during the follicular phase (1985) 10-30-664

Cytogenetic findings in 311 couples with infertility and reproductive disorders (1983) 10-30-1809

Q 10. 31 We are finding the investigation and treatment of our fertility problems to be ever more stressful. Can stress be a cause of infertility?

Inevitably the longer people try for a baby the greater the stress that they endure. Friends and family seem to produce babies without difficulty and the media highlight happy couples with their families. There has been quite a lot of research in this area. Surprisingly, no consistent relationship between stress and fertility has been found.

References:

The fertility problem inventory: Measuring perceived infertility-related stress. (1999) 10-31-2722

Distress and reduced fertility: A follow-up study of first-pregnancy planners. (1999) 10-31-2721

The experiences of couples who have had infertility treatment in the United Kingdom: Results of a survey performed in 1997. (1999) 10-31-2617

Q 10. 32 How can we determine which fertility unit is likely to be the best for us?

Society and purchasers, in all walks of life, are being trained to believe in effectiveness measurements often using arbitrary league tables. The success rates of infertility treatments are difficult to compare as there is a variety of factors associated with infertility with couples having a spectrum of severity. These factors include:

• age of each partner.

• cause of the infertility.

• duration of infertility.

• previous treatments.

There is a rapidly increasing number of treatments and a variety of protocols for each treatment. Finally, success may be reported in terms of biochemical pregnancy (a positive pregnancy test that may be performed between 9 and 21 days after the possible conception day), clinical pregnancy (evidence of a viable pregnancy on early ultrasound), ongoing pregnancy, and live births. Live birth rates may overstate success as this may include multiple births.

These problems are well recognised and useful attempts to satisfy the need for an overview have been made. Whilst high-tech assisted conception techniques may provide higher success rates per cycle, they are completely unnatural and highly invasive. Furthermore, assisted conception has a high incidence of multiple pregnancies that are prone to obstetric and neonatal complications.

We believe that couples must be provided with unbiased information so that they can, as far as economic restrictions allow, follow the treatment path of their choice. There is a need for better organisation and integration of resources to ensure that simple, less invasive and more economical investigations and treatments are fully utilised before resorting to “high-tech” options simply because they may be more modern and receive wider media coverage.

Finally, when choosing a fertility unit, it should be remembered that whereas ultimate success is a fundamental objective, the care provided by the fertility team is important and you may find that your general practitioner, friends or family are able to advise you.

Q 10. 33 Where can I obtain more information?

American Society for Reproductive Medicine

Q 10. 34 Could I have some useful Web sites?

Evaluation of the quality of Web sites is discussed in Q4.27. You may find that several general women’s health sites may help you (Q4.28). The following are more specialised Web sites on topics found in this chapter:-

This page was last updated on 19-Jun-2002

References:

Use of the Internet by infertile couples. (2000) 10-34-3156

Q 10. 1 What are the objectives of infertility treatment?

Q 10. 2 Why have I been advised to take folic acid supplements?

References:

Q 10. 3 Although my ovaries have eggs in them, my tests show that I am not releasing them (anovulation). How can we induce ovulation?

Q 10. 4 If I take drugs to induce ovulation (ovulation induction), are there any risks?

References:

Q 10. 5 How is ovulation induction treatment monitored?

References:

Q 10. 6 How does clomiphene citrate (Clomid) work?

References:

Q 10. 7 How effective is clomiphene?

References:

Q 10. 8 Could I experience any problems whilst taking clomiphene?

References:

Q 10. 9 Is there any advantage in having an injection of HCG to ensure ovulation?

References:

Q 10. 10 How does tamoxifen work?

References:

Q 10. 11 How can hyperprolactinaemia be treated?

References:

Q 10. 12 How does metformin work for infertility associated with PCOS (Polycystic Ovary Syndrome)?

References:

Q 10. 13 How do gonadotrophins work?

References:

Q 10. 14 What are the risks for me if I receive gonadotrophin therapy?

References:

Q 10. 15 What are recombinant gonadotrophins?

References:

Q 10. 16 What is ovarian hyperstimulation syndrome (OHSS)?

References:

Q 10. 17 How is ovarian hyperstimulation syndrome treated?

References:

Q 10. 18 How does electrocautery (ovarian drilling) work for infertility associated with polycystic ovary syndrome (PCOS)?

Bibliography:–

Q 10. 19 I have been found to have endometriosis. How should this be treated to improve my chance of conceiving?

Q 10. 20 Tests have shown that I have problems with my Fallopian tubes. What can be done about this?

References:

Q 10. 21 I have fibroids. How should these be treated to improve my fertility?

References:

Q 10. 22 My post-coital test has shown that my mucus is stopping the sperm from swimming (mucus hostility). What can be done?

References:

Q 10. 23 When can intrauterine insemination (IUI) improve our chance of achieving a pregnancy?

References:

Q 10. 24 What is in vitro fertilisation (IVF) and embryo transfer (ET).

References:

Q 10. 25 What is intracytoplasmic sperm injection (ICSI)?

References:

Q 10. 26 How do tubal surgery and IVF compare?

References:

Q 10. 27 What are egg donation and egg sharing?

References:

Q 10. 28 What is selective embryo transfer?

References:

Q 10. 29 Investigations have shown no obvious cause for our difficulty achieving a pregnancy. Are there any treatments for our unexplained infertility?

References:

Q 10. 30 We have tried a variety of treatments but we still have not achieved a pregnancy. Why should this be?

References:

Q 10. 31 We are finding the investigation and treatment of our fertility problems to be ever more stressful. Can stress be a cause of infertility?

References:

Q 10. 32 How can we determine which fertility unit is likely to be the best for us?

Q 10. 33 Where can I obtain more information?

Q 10. 34 Could I have some useful Web sites?

References:

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