Anovulation

Women should be made aware of potential risks of multiple pregnancy and ovarian hyperstimulation. Male factor problems and tubal pathology should be excluded. In the absence of a history suggestive of tubal disease it may be reasonable to defer formal tubal patency tests for three cycles to allow less invasive treatment options such as clomifene to be used.

WHO TYPE I

In women with weight loss associated amenorrhoea, treatment should be deferred until a target BMI of 20

kg/m2 is reached. The most physiological treatment of WHO type I anovulation or hypothalamic amenorrhoea is with pulsatile administration of GnRH agonists administered through a portable battery-operated pump (Filicori et al. 1994). Observational studies suggest that cumulative pregnancy rates of 80-90% over 12 cycles of treatment can be achieved by means of GnRHa at a dose of 15-20 p,g sub-cutaneously or 2.5-5 p,g intravenously. The intravenous route requires lower doses of GnRH, maintains a better physiological hormonal profile and provides higher rates of ovulation. Monitoring is performed by means of serum oestrogen and pelvic ultrasound. Luteal phase support is provided by means of human chorionic gonadotriphin (hCG) injections. Despite high success rates and a reduced risk of multiples, GnRH pumps may be unpopular with some women due to concerns about inconvenience and pump failure.

WHO TYPE II (PCOS) Weight loss and dietary measures

Weight loss should be the first line of treatment in obese women with anovulation due to PCOS. Central obesity and high BMI are important predisposing factors for insulin resistance, hyperinsulinaemia and hyperandroge-naemia. Effective treatment of obesity can reverse these

Insulin Pump Overweight Women
Fig. 45.3 Treatment of infertility.

effects and facilitate the effects of ovulation induction agents. In obese women with PCOS a loss of 5-10% of body weight may be enough to restore reproductive function in 55-100% women within 6 months (Clark et al. 1995).

Clomifene citrate

Clomifenecitrateis an orally activesynthetic non-steroidal compound with oestrogenic as well as anti-oestrogenic properties, which has traditionally been the treatment of choice in women with anovulatory PCOS. It displaces oestrogen from its receptors in the hypothalamic-pituitary axis, reduces the negative feedback effect of oestrogen and encourages GnRH secretion. It is administered in an initial daily dose of 50 mg on days 2-6 of a spontaneous or induced menstrual period. The dose can be increased by 50 mg per day till ovulation is achieved, up to a maximum of 150 mg per day. Couples are advised to have intercourse every other day from day 9 of the cycle for at least one week. A course of 6 to 12 cycles can be used in women who respond to the drug. It is necessary to monitor follicular response, at least in the first cycle of treatment, with TV scans to minimize the risk of multiple pregnancy. Mid-luteal progesterone levels are checked in each cycle. Ovulation is expected to occur in 80% and pregnancy in 35-40% women on clomifene (Imani et al. 2002). Approximately 20-25% of women show no response to clomifene citrate and are considered to be resistant.

Adverse reactions

Anti-oestrogenic effects include thickening of cervical mucus and hot flushes in 10% of women. Other side effects include abdominal distension (2%), abdominal pain, nausea, vomiting, headache, breast tenderness and reversible hair loss. Clomifene has a mydriatic action that can result in blurred vision and scotomas in 1.5% of women. These changes are reversible. Significant ovarian enlargement

Table 45.15 Classification of OHSS

Ultrasound

Severity

Clinical findings

picture

Mild

Abdominal bloating with some

Ovaries less

pain

than 8 cm

Moderate

Nausea, vomiting and increased

Ovarian size

abdominal discomfort

8-12 cm

Evidence of ascites

Severe

Clinical ascites ± hydrothorax

Ovaries over

with hypovolemia, oliguria (with

12 cm

normal serum creatinine),

Ascites

haemoconcentration (>45%),

leucocytosis (>15,000/ml) and

liver dysfunction

Critical

Tense ascites, haematocrit >55%,

Ovaries over

leucocytosis > 25,000/ml,

12 cm

oliguria (with raised serum

Gross ascites

creatinine), renal failure,

thromboembolic complications

Adult Respiratory Distress

Syndrome may be seen

Adapted from: RCOG Guideline no 5, 1995.

Adapted from: RCOG Guideline no 5, 1995.

occurs in 5% but ovarian hyperstimulation syndrome (OHSS) is rare (<1%). The multiple pregnancy rate associated with clomifene is 7-10%. Most multiples are twins. A putative link with ovarian cancer has been described in women receiving more than 12 cycles of clomifene.

Tamoxifen

Tamoxifen has a structure similar to clomifene. The recommended dose is 20-40 mg per day from day 3, for 5 days. Pregnancy rates with tamoxifen are similar to those obtained with clomifene (OR 1.00 95% CI 0.48, 2.09) (Beck et al. 2005) and it may have a less potent anti-oestrogenic action on cervical mucus.

Gonadotrophins

Treatment with gonadotrophins is contemplated when women either do not respond to clomifene or fail to conceive after 6-12 ovulatory cycles. Preparations in common use include recombinant FSH or purified urinary human menopausal gonadotrophin which contains FSH as well as LH. Gonadotrophin regimens include a standard step-up protocol, chronic low-dose step-up protocol and step-down protocol. Acceptable cumulative conception rates have been achieved with standard step-up treatment starting with a dose of 150 IU/day. Due to the increased sensitivity of the PCO to gonadotrophins, this regimen carries a 34% risk of multiple pregnancy and 4.6% risk of OHSS (Homburg, 2003). Therefore a low-dose FSH

Table 45.16 Risk factors for OHSS

Women under 30 years

Low BMI

PCOS

Use of GnRH agonists in combination with gonadotrophins Use of exogenous hCG either as ovulatory trigger or luteal support

Endogenous surge of hCG due to pregnancy Many small and intermediate follicles (<14 mm) High E2 level (>9000 pmol/l)

Rapid increase in oestradiol levels (more than 75% increase from previous day) Large number of oocytes (>20) collected in IVF/ICSI cycles

Adapted from: Whelan and Vlahos, 2000.

regimen is usually used to reduce the risk of multiple follicular development (Homburg, 2003). A low starting dose of 75 IU is administered for 14 days, followed by small incremental dose increases, when necessary, at intervals of not less than 7 days, until follicular development is initiated (Homburg, 2003). This dose is then continued until 1-2 leading follicles >17-18 mm are identified. Compared to the conventional regimen, the low-dose step-up regimen has been shown to yield slightly better pregnancy rates (40 versus 24%) while reducing the incidence of OHSS and multiple pregnancies. Unifollicular ovulation occurs in 74% of cases (Homburg, 2003). A systematic review (Nugent et al. 2005) found no significant difference between human menopausal gonadotrophin (HMG) and urinary FSH in terms of pregnancy rate per cycle (0.89, 95% CI 0.53-1.49). Similarly no differences in pregnancy rates have been found between the use of recombinant FSH and urinary FSH (Homburg, 2003). In women with PCOS treatment with gonadotrophins results in cumulative pregnancy rates of 40-50%, a miscarriage rate of between 25% and 30% and a 1-2% risk of serious OHSS (Tables 45.15 and 45.16).

GnRH analogues in ovulation induction

GnRH agonists have been used in conjunction with gonadotrophins to achieve pituitary downregulation and to facilitate cycle control. There are few data to support the routine use of this practice. A systematic review of three randomized controlled trials (RCTs) failed to reveal any added benefit associated with the use of GnRH agonists along with gonadotrophins in terms of pregnancy rates (OR 1.50; 95% CI 0.72-3.12) (Hughes et al. 2000).

Metformin

The strong association between anovulation and insulin resistance/hyperinsulinaemia has led to speculation that lowering insulin levels would lead to improvement in the clinical and metabolic profile of women with PCOS. While this could be achieved by weight loss alone, an insulin sensitizing agent like metformin was felt to be particularly suitable. Metformin is an oral biguanide, which has been used for the treatment of hyperglycaemia in maturity onset diabetics but which does not lower glucose levels in euglycaemic subjects. Its actions include decrease in insulin levels, lowering of circulating total and free androgen levels and improvement in the clinical sequelae of hyperandrogenism. A systematic review (Lord et al. 2003) has shown that metformin is more effective in achieving ovulation in women with PCOS in comparison with a placebo (OR 3.88, 95% CI 2.25-6.69). In combination with clomifene, it is more effective than clomifene alone in achieving ovulation (OR 4.41, 95% CI 2.37-8.22) as well as pregnancy (OR 4.40, 95% CI 1.96-9.85). Metformin has been shown to have a beneficial effect on fasting insulin, blood pressure, low-density lipoprotein cholesterol but evidence of any effect on body mass ratio or waist/hip ratio is lacking. It is associated with a higher incidence of nausea, vomiting and other gastrointestinal disturbances and can cause lactic acidosis in patients with deranged renal function. The evidence regarding the safety and efficacy of metformin has been encouraging so far (Homburg 2003). It remains to be proven whether metformin will emerge as the drug of choice in all infertile women with PCOS. Metformin is currently unlicensed for use in PCOS and although preliminary data suggest that the drug is safe in pregnancy (and may even decrease miscarriage rates), (Homburg, 2003) more data on efficacy and safety from randomized trials are awaited. Other serum insulin lowering compounds, like the glitazones (rosiglitazone and pioglitazone) and d-chiro-inositol are currently under investigation.

Laparoscopic ovarian drilling

Laparoscopic ovarian drilling (LOD) by diathermy or laser is a further treatment option for women with anovulation associated with PCOS. The procedure appears to be more successful in women who are slim and have high LH levels; the mechanism for its effect is unknown. A unipolar coagulating current is used to deliver four punctures to a depth of 4 mm in each ovary. A Cochrane review (Farquhar et al. 2000) showed that ongoing cumulative pregnancy rates following LOD were similar to those obtained with 3-6 cycles of gonadotrophins (OR 1.27, 95% CI 0.77,1.98). Multiple pregnancies were reduced in women treated by ovarian drilling (OR 0.16, 95% CI 0.03, 0.98). The principal advantages of ovarian drilling include monofollicular ovulation resulting in fewer multiple pregnancy rates.

Aromatase inhibitors

Aromatase inhibitors have been used as alternatives to clomifene in view of their lack of anti-oestrogenic effects. They suppress oestrogen production and mimic the central reduction of negative feedback by ovarian oestrogen. Data from early trials confirm the effectiveness of Letro-zole, the most commonly used agent (Homburg 2003). Evidence from larger trials is awaited.

WHO TYPE III

Egg donation may be the only option for patients with ovarian failure. This is discussed in greater detail later in the chapter on assisted reproduction (Chapter 46).

HYPERPROLACTINAEMIA

Prolactin secretion is regulated by the tonic inhibitory control of dopamine. Bromocriptine, which has a dopamine like action, is effective in hyperprolactinaemia. It shrinks 80% of macroadenomas, and can help to normalize prolactin values in 80-90% and restore ovulation in 70-80% of women. Long-term treatment with bromocriptine results in pregnancy rates of 35-70% per woman. Due to its short half-life, bromocriptine needs to be administered two to three times a day. Side effects including nausea, headache, vertigo, postural hypotension, fatigue and drowsiness can be minimized by initiating treatment with a low dose of bromocriptine (1.25 mg) at bedtime with a snack, and gradually increasing up to 2.5 mg three times a day with food over 2 to 3 weeks. Cabergoline and Quinogolide are newer dopamine agonists which have recently been licensed for treatment of hyperprolactinaemia. Fewer side effects and longer half-lives allow a once daily dose for quinogolide and a twice weekly dose for Cabergoline. Data from two randomized controlled trials have shown cabergoline to be more effective than bromocriptine in restoring normoprolactinaemia and ovulation.

Treatment of hyperprolactinaemia is mainly medical. In rare cases surgery may be considered in women with pituitary tumours who despite normalization of prolactin levels do not show adequate tumour shrinkage. Alternatively it may be considered in patients with large macroade-nomas who are intolerant or resistant to drug treatment. Despite the invasive nature of surgery, its effects are modest. Post surgery, prolactin values return to normal in 50% of microadenomas and 10-15% of macroadenomas.

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