INFERTILITY 1. A couple investigated for infertility were categorized as unexplained infertility. Summarize the options available to them.

Common mistakes Discussing the causes of infertility- there is no need to list the causes of infertility as the question explicitly demands summarizing options for a particular type of infertility - the unexplained type Do not discuss the contributions of every factor involved in infertility Take a history and doing a physical examination is irrelevant. The couple have already been investigated and categorized as unexplained!! Details of infertility treatment in general, for example ovulation induction regimens in women with anovulation, in vitro fertilization with embryo transfer (IVF-ET), etc. These are irrelevant to this question A good answer will include some or all of these points What is the definition of unexplained infertility and its prevalence Factors that may influence outcome (chances of a successful outcome) - secondary infertility has a better prognosis than primary Counselling - the first important stage: supportive; success rate; influence of natural conception rates superimposed as infertility Assisted reproductive techniques - IVF-ET, gamete intraFallopian transfer (GIFT), artificial insemination by husband (AIH), artificial insemination by donor (AID); expensive; complications; psychological problems with failure Surrogacy Sample answer Unexplained infertility is defined as infertility in which all investigations have failed to identify a cause. This definition depends to a large extent on the extent and complexity of the facilities that are available for the investigations. These are more likely to be more extensive in tertiary centres than in primary or secondary units.

Prevalence is thought to vary from 10 per cent to 39 per cent of all infertile couples (Templeton and Penney, 1982). It is well-recognized that the outcome of unexplained infertility depends on various factors. These include the age of the female patient, the duration and type of infertility. If the woman is over the age of 35, the success of expectant management is poor. Hull et al. (1985) showed that the chances of spontaneous conception are closely related to the duration of infertility and whether it is primary or secondary in nature. The first option for any couple with this diagnosis, therefore, is counselling and reassurance. The eventual pregnancy rate after three years' expectant management is between 60 per cent and 70 per cent (Hull et al., 1985). In this option, sympathetic expla nations of the diagnosis and the success rate of expectant management are offered to th couple. The most likely couple to succeed with this option is the young one. This option is frustrating at the best of times, not only to the couple but also to the physician. For older women the success rate is lower simply because age has an important effect on spontaneous conception rates. The next option for the couple is assisted reproduction techniques for infertility Although there is no evidence to indicate that detailed investigations and treatment have a better success rate, it may provide a psychological boost to the couple - the perception that something is being done to overcome the problem. The drawback to this option is that pregnancies occurring during this time could be wrongly attributed to the investigations and empirical treatment rather than to natural conception. Options include artificial insemination with the husband's semen (AIH). This is inexpensive and likely to be acceptable to the couple. In vitro fertilization and embryo transfer (IVF-ET) may also be offered. Here, superovulation is induced and, after harvesting the eggs, fertilization is facilitated in vitro and the fertilized embryo transferred into the uterus. The advantage of this technique is that fertilization is guaranteed and extra embryos may be stored for further attempts. However, this is a very expensive option and one whose failure may be associated with many psychological problems. A third intervention option is gamete intra-Fallopian transfer (GIFT). Again, this is an invasive option. Some couples may be offered ovulation induction but allowing `natural conception' to take place. This option ensures that ovulation (and possibly multiple ovulation) has occurred. It is expensive and may be complicated by ovarian hyperstimulation syndrome, with associated severe morbidity and sometimes mortality. The last option for the couple is adoption. Adopting may sometimes remove the anxiety associated with attempting to conceive and result in a natural conception. Whatever the case, there is the need to be more pro-active in the older than the younger couple. Those with primary infertility have a lower success rate with expectant management than those with secondary infertility. Where the duration of infertility is less than three years, expectant management is associated with an eight per cent success rate. 2. Critically assess the methods of assessing tubal function in the investigation of infertility

3. Evaluate your options for ovulation in a 25-year-old patient with polycystic ovary syndrome. Common mistakes Induction of ovulation and treatment for infertility Discussing options for infertility treatment Concentrating on drug therapy only Treatment of male infertility Details of IUF/ET or GIFT etc. A good answer will include some or all of these points Induction of ovulation - methods: weight loss; medical or surgical options Anti-oestrogens - clomifene citrate or cyclofenil, gonadotrophins (Nletrodin) Gonadotrophin-releasing hormone (GnRH) analogues and gonadotrophins Metformin Surgical Ovarian diathermy/laser Wedge resection of the ovary Sample answer Polycystic ovary syndrome is one of the most common gynaecological endocrinological disorders. Infertility is one of the symptoms with which these patients present and it is commonly due to anovttlation. Ovulation induction in polycystic ovary syndrome may be achieved through medical or surgical options. However, as some of these patients are overweight, simple measures such as weight loss may be effective in inducing ovulation. This has the added advantage that it does not require any medication, is free of side-effects and is inexpensive. In addition, if successful, conception rates are higher following induction of ovulation as a result of weight loss than that of other methods. Of the medical methods of inducing ovulation, clomifene citrate is the most commonly used. This is an anti-oestogen, usually administered in the early menstrual phase. It is inexpensive and induces ovulation successfully in about 30-40 per cent of patients with polycystic ovary syndrome, although that rate may be as high as 80 per cent in properly selected patients. The six months' cumulative conception rate, where ovulation has been successfully induced, is similar to that of normal fertility (60 per cent) with most occurring in the first six ovulatory cycles. It has the added advantage that the multiple pregnancy rate is only five to 10 per cent and significant ovarian hyperstimulation syndrome is rare compared to that after ovulation induction with gonadotrophins. Unfortunately, because of the anti,estrogenic effects, clomifene citrate may induce ovulation but not result in successful pregnancy. Often, therefore, patients may have to take multiple courses before pregnancy can be achieved.

Where clomifene citrate has been unsuccessful in inducing ovulation and pregnancy, cyclofenil could be the next option. It is also an anti-oestrogen but it has less antioestrogenic effects on the cervical mucus. It may theoretically be associated with higher pregnancy rates than clomifene citrate. However, cyclofenil is more expensive and associated with more sideeffects when compared to those of clomifene citrate. Human menopausal gonadotrophins (HMG) and pure follicle-stimulating hormone (FSH) (pergonal, normagon or metrodin), extracted from the urine of postmenopausal women, are effective but more expensive methods of ovulation induction in patients with polycystic ovary syndrome, preferably when anti-oestrogen agents have failed. They are available as FSH and luteinizing hormone (LH) (for example, pergonal and normagon) of pure FSH (for example, metrodin). Recombinant FSH is now available, with the advantage of being free of extraneous proteins to which some patients may develop allergic reactions or antibodies. This is an effective but more expensive method of ovulation induction than the previous two options. They also have to be administered parenterally (usually daily and starting in the menstrual phase). Ideally, the patient should have follicular tracking and serial oestradiol monitoring to time the administration of human chorionic gondadotrophins (HCG), in order to minimize the risk of multiple pregnancies and ovarian hyperstimulation syndrome. A combination of these is certainly more expensive than the previous oral regimens. As these patients are more sensitive to HMG, treatment is usually initiated on lower doses (75 IU) and monitored every five days. The 12 months' cumulative pregnancy rate following this regimen in polycystic ovary syndrome patients is much higher than in those with hypo-pituitary dysfunction. The risk of ovarian hyperstimulation syndrome is one to two per cent, whereas there is a 25 per cent incidence of pregnancies of higher orders. Unfortunately, the miscarriage risk associated with this method of induction of ovulation is between 32 per cent and 40 per cent. For this patient, the surgical methods of ovulation induction include laparoscopic laser or diathermy drilling of the ovaries. Although successful, the main disadvantages of the surgical options are the short-lasting effects of treatment. The procedure itself is expensive and involves a lapatoscopy and hospital care even if this only during the time of treatment. There are associated complications of the procedure and the ever-present risk of adhesion formation. In skilled hands, this may be best performed at the time of laparoscopic assessment of tubal function. The original method of ovulation induction in patients with polycystic ovary syndrome was wedge resection of the ovary. Although this has generally been superseded by modern techniques, it may still be considered in some developing countries. Very recently, metformin has been being used to induce ovulation in overweight diabetic women. This must be an option in this patient if she is obese. The pregnancy rate after induction of ovulation by weight loss is higher than in that after other methods of ovulation induction.

4. What steps will take to minimize the risk of ovarian hyperstimulation syndrome and how will you recognize it?
Common mistakes

Classification and details of ovarian hyperstimulation syndrome Treatment and management of the causes of ovarian hyperstimulation syndrome Mentioning irrelevant points, for example, ovarian hyperstimulation syndrome does not occur with gondadotrophin-releasing hormone (GnRH) analogues (this is not true and if you are uncertain do not mention it). Ovarian hyperstimulation syndrome occurs in natural cycles! Vaginal examination is contraindicated in ovarian hyperstimulation syndrome Scanning before induction of ovulation to determine suitability for induction. investigations for ovarian hyperstimulation syndrome Inaccurate facts, for example, features of ovarian hyperstimulation syndrome hirsutism, irregular periods and vaginal bleeding Use of clomid for more than six months inadvisable lation syndrome Only occurs in polycystic ovary syndrome gonadotrophins has occurred Define the features of ovarian hyperstimulation syndrome (enlarged ovaries, abdominal distension, nausea, vomiting, diarrhoea, and in severe forms, ascites, pleural effusions, hypovolaemia, hypotension and polycythaemia) Ovarian hyperstimulation syndrome results from superovulation. Potentially fatal Predisposing factors: large number of follicles (especially induced by gonadotrophins and beta-human chorionic gonadotrophins, (3HCG); (3HCG administration; younger patients; pregnancy - four times higher incidence in conception cycles. Pregnancy increases x3 in ovarian hyperstimulation syndrome cycles; low body mass index (weight) (BMI <19); polycystic ovary syndrome Minimizing the risk Serial follicular tracking to ensure no HCG administration for more follicles Oestradiol levels >6000 pmol, do not administer PHCG Advice against sexual intercourse if oestradiol levels high or large number of follicles Progestogens rather than (3HCG to support pregnancy Ovarian drilling /diathermy for polycystic ovary syndrome Clomid rather than gonadotrophins Human menopausal gonadotrophins (HMG) + gonadotrophin-releasing hormone (GnRH) agonists increase the prevalence of ovarian hyperstimulation syndrome Recognition Symptoms - mild, moderate or severe (abdominal pain, vomiting, chest pain enlarged abdomen) Ultrasound - follicles, ascites Biochemistry - deranged urea output, pleural effusion - chest Xray (CXR)

A good answer will include some or all of these points

Sample answer

Ovarian hyperstimulation syndrome is a complication of induction of superovulation. Its incidence varies from approximately 10 per cent to 20 per cent, depending on severity. This includes mild, through moderate, to severe varieties. Ovarian hyperstimulation syndrome consists of ovarian enlargement, abdominal distension, ascites, nausea, vomiting and diarrhoea, and in severe forms, pleural effusion, hypovolaemia, hypotension and polycythaemia. If improperly managed, it could be fatal. To minimize the risk of hyperstimulation, the factors predisposing to ovarian hyperstimulation syndrome must be identified. In the the younger patient, polycystic ovary syndrome, low body mass index (BMI <19), beta-human chorionic gonadotrophin ((3HCG) administration, high serum oestradiol levels during ovulation induction, a larger number of follicles (> 18-20 mm in diameter) during ovulation and pregnancy. Pregnancy is three times more likely in ovarian hyperstimulation syndrome cycles. Minimizing the risk of ovarian hyperstimulation syndrome, therefore, must involve reducing the predisposing factors. First, ovulation induction is best undertaken by drugs that are least likely to induce the condition. For example, the use of anti-oestrogen agents, such as clomifene citrate instead of gonadotrophins. However, this may not necessarily be the case, as these drugs may be ineffective. Alternatives to gonadotrophins, such as ovarian drilling, must also be considered. Where gonadotrophins are employed, the ovulation induction process must be monitored closely. This will include follicular tracking with ultrasound to ensure that there are not too many follicles ready to rupture. This can be complemented with serum oestradiol estimations. If the number of follicles above 12 mm in diameter is more than 15, or serum oestradiol levels are above 2000 pg/ml, then (3HCG should be withheld. This will delay, or prevent, release of the ova from the follicles. In some cases, it has been suggested that delaying rather than omitting the PHCG may also minimize the risk of ovarian hyperstimulation syndrome. Where ovulation induction is for a natural conception, advising against sexual intercourse will minimize the risk of ovarian hyperstimulation syndrome. This will prevent pregnancy and therefore reduce the chances of ovarian hype rstimulation syndrome developing. If pregnancy does occur, the use of progestogens rather than HCG to support the early phase of pregnancy will significantly minimize the risk of ovarian hyperstimulation syndrome. Ovulation induction with gonadotrophin-releasing hormone (GnRH) agonists with HCG or HMG is associated with a lower risk of ovarian hyperstimulation syndrome compared to the use of HMG and HCG. Used in a pulsatile fashion, this has been shown to result in successful pregnancy without the risk of developing the condition. GnRH agonists with HCG or HMG may be used in patients who have raised oestradiol levels during induction of ovulation with gonadotrophins. Imoedemhe et al. (1991) used eight-hourly intranasal buserelin in patients with >4000 pg/ml oestradiol levels and achieved a 22 per cent pregnancy rate with no case of ovarian hyperstimulation syndrome. Alternatively, follicular aspiration may be used. Pregnancies after in vitro fertilization (1VF) are rarely complicated by ovarian hyperstimulation syndrome. This is because of aspiration of the follicles. Therefore, where there are many follicles above the threshold diameter, repeated aspiration will minimize the risk of ovarian hyperstimulation syndrome. Although other methods of minimizing the risk of ovarian hyperstimulation syndrome have been employed, such as intravenous (i.v.) administration of albumin and also

corticosteroids, these are not commonly used. The most effective method of minimizing this complication of superovulation is to monitor the patient closely and to offer interventions that will minimize it. It is also important to identify early symptoms and signs of ovarian hyperstimulation syndrome and to take the steps necessary to prevent progression. Early symptoms include abdominal pain, vomiting chest pain and an enlarged abdomen. Ultrasound monitoring of follicles during superovulation with gonadotrophins and ready investigation for biochemical derangements suggestive of early ovarian hyperstimulation syndrome are essential. Close monitoring of the patient's urine output may also indicate the early onset of ovarian hyperstimulation syndrome. Once these are identified, avoiding (3HCG will minimize the severity of the condition. 5. A couple attending the infertility clinic have been investigated and the husbands semen analysis was described as oligozoospermic. Evaluate the options available to the couple.