Disorders of ovulation

Disorders of ovulation are divided into four categories, defined by the World Health Organization (WHO):

Anovulation is usually associated with amenorrhoea or oligomenorrhoea. Alterations in the menstrual cycle are commonly associated with periods of stress and also with excessive weight gain or obesity, worsening the impact of PCOS on ovulation, or at the other extreme, with anorexia nervosa or excessive exercise leading to hypogonadal (type I) anovulation.

Tubal factors

The Fallopian tube must first collect the ovum from its site of ovulation from the ruptured Graafian follicle and then transport the ovum to the ampullary segment, where fertilization occurs. The fertilized ovum must then be transported to the uterine cavity to arrive at the correct point in the menstrual cycle at which the endometrium becomes receptive to implantation (the ‘implantation window’). Tubal factors account for about 10–30% of cases of infertility: this figure varies considerably according to the population involved. Occasionally, congenital anomalies occur but the commonest cause of tubal damage is infection. Infection may cause occlusion of the fimbrial end of the tube, with the collection of fluid (hydrosalpinx) or pus (pyosalpinx) within the tubal lumen (Fig. 17.1).

The commonest cause of acute salpingitis in UK is infection with Chlamydia trachomatis, but it may also result from infection with other organisms such as Neisseria gonorrhoeae, Escherichia coli, anaerobic and haemolytic streptococci, staphylococci and Clostridium welchii. The incidence of tubal damage is approximately 8% after the first episode of pelvic infection, 16% after two and 40% after three episodes. Tubal or uterine tuberculosis has begun to be seen more frequently in the UK in the immigrant population or their relatives.

Disorders such as appendicitis associated with peritonitis or inflammatory conditions including Crohn’s disease or ulcerative colitis can result in peritubal and peri-ovarian adhesions, leaving the internal structure of the Fallopian tube relatively unaffected.

Uterine factors

Implantation is less likely to occur if there is distortion of the uterine cavity due to submucous fibroids or congenital abnormalities such as an intrauterine septum. These disorders are often amenable to surgical correction. Subserous or entirely intramural fibroids do not appear to affect implantation. The effect of adenomyosis on implantation is unclear, although the disorder has been linked to recurrent implantation failure and miscarriage. Intrauterine adhesions or synechiae following over-vigorous curettage or infection (Asherman’s syndrome) result in inadequate endometrial development, absent or light periods and recurrent implantation failure.

Cervical factors

At the time of ovulation, endocervical cells secrete copious, clear, watery mucus, with high water content and elongated glycoprotein molecules containing channels that facilitate passage of spermatozoa into the uterine cavity. Sperm penetration occurs within 2–3 minutes of deposition. Between 100 000 and 200 000 sperm colonize the cervical mucus and remain at this level for approximately 24 hours after coitus. Approximately 200 sperm eventually reach the Fallopian tube. After ovulation, mucus produced by the cervix under the influence of progesterone is hostile to sperm penetration. Cervical infection or antisperm antibodies in cervical mucus or seminal plasma, can inhibit sperm penetration and result in subfertility.

Detection of ovulation

The assessment of ovulation depends on the menstrual history. In the presence of a regular menstrual cycle ovulatory status can be investigated by changes in basal body temperature, cervical mucus or hormone levels, by endometrial biopsy or by ultrasound. However, measurement of basal body temperature (BBT) is difficult for many women to achieve and requires daily charting, increasing stress with a daily reminder of failure to conceive. Hence measurement of BBT is no longer recommended. Similarly, many women find assessment of cervical mucus changes difficult and challenging and this method is also not recommended. Ovulation can be inferred by detection of the LH surge in blood or urine, with a peak that occurs approximately 24 hours before ovulation. Modern commercially available LH surge detection kits can provide reassurance and allow timing of intercourse. Formation of the corpus luteum can be demonstrated by measurement of serum progesterone in the luteal phase of the cycle. A mid-luteal concentration above 25 nmol/L is usually accepted as evidence of ovulation, although values vary from laboratory to laboratory.

Investigation of tubal patency

It is essential to establish tubal patency before beginning ovulation induction or intrauterine insemination. Tubal patency need not be established if the couple are to proceed directly to IVF if, for example, there is a severe male factor. However, uterine anatomy should then be checked with high-resolution transvaginal ultrasound or hysterosalpingography (HSG).

Hysterosalpingography

A radio-opaque contrast medium is injected into the uterine cavity and Fallopian tubes. General anaesthesia is unnecessary. The contrast medium outlines the uterine cavity and will demonstrate any filling defects. It will also show whether there is evidence of tubal obstruction and the site of the obstruction (Fig. 17.2). HSG should be performed within the first 10 days of the menstrual cycle to avoid inadvertent irradiation of a newly fertilized embryo. Women should be screened for C. trachomatis infection or given appropriate antibiotic prophylaxis before HSG in order to reduce the risk of reactivation of infection leading to pelvic abscess formation.

Laparoscopy and dye insufflation

Laparoscopy enables direct visualization of the pelvic organs and allows assessment of pelvic pathologies such as endometriosis or adhesions. Methylene blue is injected through the cervix in order to test tubal patency. Laparoscopy can be combined with hysteroscopy to assess the uterine cavity. A ‘see-and-treat’ policy allows for rapid surgical treatment of minor degrees of endometriosis or adhesions, although surgery that may result in damage to pelvic structures is better left to another occasion to allow full discussion of the implications of surgery to take place with the patient and her partner. Laparoscopy almost invariably requires general anaesthesia and there are small but significant risks of damage to pelvic structures including bowel, bladder and ureter at laparoscopy, so less invasive methods are preferred as first line investigations unless there is a specific indication, such as a history of pelvic inflammatory disease or appendicitis with peritonitis (Fig. 17.3).

Investigation of cervical factor infertility

‘Cervical factor’ infertility tests, such as postcoital tests, are not recommended in the routine investigation of the infertile couple because of the lack of established normal criteria and poor correlation between findings and fertility. Modern treatments for infertility such as intrauterine insemination or IVF will bypass cervical mucus and circumvent any possible cervical causes for infertility.

Investigation of the male partner

The most useful investigation of the male partner is by semen analysis (Box 17.1). Semen should be collected by masturbation into a sterile container after 3 days abstinence and examined within 2 hours of collection. The sample is best collected in a private facility adjacent to the andrology laboratory to avoid cooling during transportation and allow accurate identification of the male partner.

The recently revised lower reference limits and 95% confidence intervals for sperm parameters (WHO 2010) are given in Table 17.3.

The major features of the semen analysis are:

Spermatogenesis and sperm function may be affected by a wide range of toxins and therapeutic agents. Various toxins and drugs may act on the seminiferous tubules and the epididymis to inhibit spermatogenesis. Chemotherapeutic agents, particularly alkylating agents, depress sperm function and sulphasalazine, frequently used to treat Crohn’s disease, reduces sperm motility and density. Patients who are prescribed chemotherapy or pelvic radiotherapy should be offered sperm cryopreservation before treatment to allow them to start a family later in life once their disease has been successfully treated (Fig. 17.4).

Additionally, antihypertensive agents can cause erectile dysfunction and anabolic steroids used for bodybuilding may produce profound hypospermatogenesis.

Anovulation

In the presence of WHO group II anovulation with stigmata of PCOS, normal FSH and prolactin levels, the drug of choice remains clomiphene citrate. Clomiphene will produce ovulation in 80% of subjects leading to pregnancy in about one half of those who ovulate. Clomiphene is administered from day 2–6 of the cycle with an initial dosage of 50 mg/day, increased to 100 and 150 mg/day where necessary. Ovulation can be monitored by measurement of day 21 progesterone levels, although restoration of a regular menstrual cycle is frequently followed by pregnancy as ovulation resumes. Rates of twin pregnancy of 6–10% have been reported, with higher order pregnancies being reported in approximately 1 : 1000 patients. Ultrasound monitoring of follicle growth is recommended, with abstention from intercourse if there are more than two mature follicles, to reduce the incidence of multiple pregnancy. More recently, the aromatase inhibitor letrozole has been used as an oral alternative to clomiphene, with an increase in percentage of women who ovulate and possibly better pregnancy rates. However letrozole remains unlicensed for treatment of infertility.

Second-line management of anovulation may involve laparoscopic ovarian diathermy (LOD), which induces ovulation in over 70% of PCOS patients. LOD has the advantage of inducing natural mono-ovulation with a risk of multiple pregnancy no higher than background and, when successful, allowing a drug-free and more natural conception. Alternatively, ovulation may be induced with daily injection of recombinant or urinary derived FSH although this may be costly and monitoring with ultrasound and blood tests is required due to the possibility of over response and risk of multiple pregnancy. Careful management using a low-dose step up regime can produce acceptable pregnancy rates with a low multiple pregnancy rate.

Anovulation associated with hyperprolactinaemia, in the absence of macroadenoma, can be treated with a dopamine receptor agonist such as cabergoline. Cabergoline is preferred to bromocriptine due to its ease of administration and reduced incidence of side effects.

Tubal pathology

Tubal microsurgery has been almost completely supplanted by IVF in the management of tubal infertility. Laparoscopic surgery may still be necessary to perform salpingectomy or tubal clipping prior to IVF in the presence of hydrosalpynx to reduce chances of contamination of the endometrial cavity with ‘toxic’ hydrosalpyngeal secretions, or for preliminary ovarian cystectomy or myomectomy.

Salpingolysis to release peritubal adhesions still has a place if the fimbrial ends of the tubes are well preserved. However, it is important not to lose too much time if the woman is over 30 years of age. At times the blocked tubal end can be opened, i.e. salpingostomy (Fig. 17.5). There is an increased risk of ectopic pregnancy after all forms of tubal surgery.

Intrauterine insemination

Placement of a sample of sperm into the uterine cavity using a soft, flexible catheter has been performed for many years. The technique has been enhanced by preparation of the semen sample by washing and isolation of motile sperm, and by stimulation of ovulation using low dose gonadotrophins. IUI can be seen as a specific treatment for coital dysfunction and for abnormalities of cervical mucus, but is also used frequently to treat unexplained infertility and mild male factor infertility. IUI requires healthy, patent Fallopian tubes. Live birth rates in good quality centres are between 15% and 20% per cycle, although IUI remains a cost effective alternative to IVF because of the lower doses of gonadotrophins, reduced level of monitoring and simplified laboratory requirements.

In vitro fertilization and embryo transfer

In vitro fertilization and its many variants have revolutionized the management of infertility since the birth of Louise Brown in 1978. Globally, there are now more than 5 million children who have been born following IVF and generally reassuring data on safety of IVF, ICSI and embryo cryopreservation have been compiled by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine. Essentially, IVF involves stimulation of multiple ovarian follicle development using recombinant or urinary derived gonadotrophins, with concurrent use of a gonadotrophin-releasing hormone (GnRH) agonist or antagonist to prevent a premature LH surge and ovulation before oocytes are harvested. Oocytes are collected using transvaginal ultrasound guided needle follicle aspiration, with the oocytes being isolated from the follicular fluid and cultured in the presence of a washed sample of the partner’s sperm. Fertilized oocytes (embryos) can be cultured for up to 5 days, at which point they reach the blastocyst stage of division and it becomes possible to make a detailed assessment of their morphological quality. The ‘best’ one or two blastocysts are then transferred to the uterine cavity using a simple catheter, with remaining blastocysts being cryopreserved for use later if conception does not follow the fresh embryo transfer.

There are many variations on this theme – embryos can be transferred on day 2 or 3 of development rather than as blastocysts, all embryos may be cryopreserved without a fresh transfer if there is risk of ovarian hyperstimulation syndrome (OHSS) and embryos can be biopsied for pre-implantation genetic diagnosis (PGD) of chromosomal or genetic disorders with transfer only of those screened as normal. ICSI is widely used in cases of moderate to severe male factor infertility to inject a single spermatozoon directly into the cytoplasm of the oocyte, giving similar fertilization and pregnancy rates to IVF. Female age remains the main determinant of outcome and an increasing number of women are resorting to treatment with donated oocytes from younger women as a means of achieving pregnancy at a time of life when their own ovarian reserve is too low to allow them the opportunity of healthy pregnancy and live birth. Whilst treatment with donor oocytes has a high chance of a healthy live birth, the child does not have the DNA of his or her birth mother and the shortage of altruistic donors has led to development of an international market in oocytes from paid donors. Payment to oocyte or sperm donors remains illegal in UK, although at time of writing an Human Fertilisation and Embryology Authority (HFEA) consultation is underway to assess societal attitudes to this ethical dilemma.

In the UK, ART is regulated by the HFEA that oversees all aspects of IVF treatment. The HFEA has proven a useful interface between the public and Government on one hand, and IVF clinics on the other, allowing for ethical debate and imposition of ‘best practice’ in areas of clinical and laboratory safety. HFEA also collates treatment results from all clinics in UK, providing a snapshot of what can be achieved by ART. Fertilization rates after IVF are between 60% and 80% depending largely on the age of the woman, and most patients who undertake IVF will have an embryo transfer. However, implantation rates remain relatively low leading to a live birth in 30–40% of cycles in most centres.

The most frequent cause of obstetric and paediatric problems in offspring from IVF is the result of multiple pregnancy leading to premature birth. Transfer of two, three or more embryos in a single IVF cycle was commonplace in the early days of ART, but many countries, led by those in Scandinavia, have adopted a policy of single embryo transfer (SET) in the majority of IVF cycles. Multiple pregnancy rates remain at approximately 20% in UK, but are falling steadily (Table 17.4). Improved success rates from transfer of frozen embryos after cryopreservation using vitrification have made single embryo transfer a more attractive option to couples, since their chances of a live birth after sequential transfer of one fresh then one frozen embryo are equivalent to those seen after transfer of two fresh embryos, but without the risk of multiple pregnancy. The higher percentage of multiple pregnancies seen in the older patient groups reflects the lower overall chances of pregnancy, leading patients and practitioners to resort to desperate measures in order to try and achieve a pregnancy.

Treatment

If the haematocrit is below 45% and the signs and symptoms are mild, the patient can be managed at home, but where there is significant ascites as judged by ultrasound examination, she should be hospitalized. Baseline electrolyte values and liver and kidney function should be assessed. Volume expansion can be performed using human albumin, sometimes with crystalloid, and, if there is severe ascites or pleural effusion, fluid should be drained to reduce the fluid load. Drugs such as indomethacin and angiotensin-converting enzyme inhibitors may be useful in reducing the severity of the episode. Eventually, the cysts will undergo resorption, and the ovaries will return to their normal size. Further attempts at ovarian stimulation should take into account the dosage regimes used during the episode of ovarian hyperstimulation syndrome.

Donor insemination

If sperm cannot be obtained for ICSI, or if the man is a carrier of a genetic disorder that the couple wish to avoid transmitting to their child, then donor insemination should be discussed with the couple.

The implications of the procedure, from both a legal and personal point of view, should be discussed in depth, with independent counselling for both partners. Anonymity for sperm donors was removed in the UK in 2004 and the resultant shortage of donor sperm has led many couples to seek treatment overseas or to import sperm from Denmark, the US and elsewhere. Children conceived using donor oocyte or sperm collected after 2004 are legally allowed to meet their genetic parent under supervised conditions when they reach the age of 18. They can also check whether a potential partner was conceived using the same donor by referring to the HFEA database, although the name of the donor will not be released if the treatment preceded the change in the law regarding anonymity.

Waiting lists for treatment in UK are lengthy, although this does at least give adequate time for reflection.