Abstract
Folic acid should be taken at a daily dose of 400 mcg or, in those who are obese, 5 mg. There is debate about the restriction of fertility treatment to women who are overweight, although there is no doubt that obesity has a significant adverse impact on reproductive outcome. It influences not only the chance of conception but also the response to fertility treatment and increases the risk of miscarriage, congenital anomalies and pregnancy complications [1]. The British Fertility Society guidance suggests that treatment should be deferred until the BMI is less than 35 kg/m2, although in those with more time (e.g. less than 37 years, normal ovarian reserve) a weight reduction to a BMI of less than 30 kg/m2 is preferable [2]. Even a moderate weight loss of 5–10% of body weight can be sufficient to restore fertility and improve metabolic parameters.
1 Pretreatment Considerations
Folic acid should be taken at a daily dose of 400 mcg or, in those who are obese, 5 mg. There is debate about the restriction of fertility treatment to women who are overweight, although there is no doubt that obesity has a significant adverse impact on reproductive outcome. It influences not only the chance of conception but also the response to fertility treatment and increases the risk of miscarriage, congenital anomalies and pregnancy complications [1]. The British Fertility Society guidance suggests that treatment should be deferred until the BMI is less than 35 kg/m2, although in those with more time (e.g. less than 37 years, normal ovarian reserve) a weight reduction to a BMI of less than 30 kg/m2 is preferable [2]. Even a moderate weight loss of 5–10% of body weight can be sufficient to restore fertility and improve metabolic parameters.
A semen analysis should be performed before ovulation induction therapy is commenced. We recommend that tubal patency should be assessed by either hysterosalpinography (HSG) or laparoscopy before embarking upon ovulation induction therapy. There are some who believe that, if there are no firm indications (e.g. past history of pelvic infection, pelvic pain) a test of tubal patency can be delayed until there have been up to three or six ovulatory cycles. In order to minimize the risks of therapy, however, and also to ensure a cost-effective approach to treatment, we feel that an assessment of tubal patency is appropriate in every woman before commencing therapy.
2 Pituitary and Hypothalamic (WHO Group I Disorders)
Pituitary and hypothalamic causes of anovulation constitute about 5–10% of all cases of anovulation (see Chapter 4 on female fertility). In women with low body weight (e.g. anorexia nervosa), restoration of body weight may help to resume natural ovulation. A vast majority of cases presenting to a fertility clinic however, do not have frank anorexia but are usually underweight and/or exercising a little too much. There may be a delay of several months or even years before cycles are re-established after a gain in weight and many also have underlying ovulatory problems secondary to PCOS. Drugs should not be used to stimulate ovulation until a regain of weight in order to reduce the risks to the fetus of miscarriage, stillbirth and intrauterine growth restriction.
For patients with idiopathic hypogonadotrophic hypogonadism or Kallmann’s syndrome and an intact pituitary gland, ovulation may be induced with either pulsatile gonadotrophin releasing hormone (GnRH) or gonadotrophin therapy. Pulsatile GnRH may be administered subcutaneously by a miniature infusion pump, with a pulse of 15 mcg being released every 90 minutes. This is the most physiological way to achieve unifollicular ovulation, but unfortunately the therapeutic preparations of GnRH are no longer available and so we are currently unable to use these pumps.
As an alternative, parenteral gonadotrophin therapy with both FSH and LH activity can be administered as a daily injection. Urinary human menopausal gonadotrophins (hMG) contain a combination of FSH and LH while the recombinant preparations usually contain only FSH or LH activity, although newer preparations with combined recombinant FSH and LH in a single injection are now available. In women with hypothalamic hypogonadism, recombinant FSH (rFSH) alone stimulates follicular growth, but results in inadequate oestrogen production confirming the need for LH to fulfil the ‘two cell, two gonadotrophin’ requirement for ovarian steroidogenesis [3]. Therefore, in practice, hMG preparations are usually administered.
The aim of ovulation induction is to select a single antral follicle that will be able to reach the preovulatory stage with appropriate endometrial development. Serial ultrasound scanning to monitor the ovarian response is an integral part of treatment. When the follicle reaches a preovulatory size (17–18 mm diameter), a human chorionic gonadotrophin (hCG) injection is administered for oocyte maturation and to trigger ovulation. In order to minimize the chances of multifollicular development and thereby to reduce risks of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS), low-dose step-up regimens are usually employed [4]. Luteal support after ovulation induction is not required. It has been suggested that adjuvant therapy with human growth hormone is of benefit to some women in this group who had a previous poor response to gonadotrophin ovulation induction but its use is not recommended as it does not improve live birth rates [5].
3 Hyperprolactinaemia
The management of hyperprolactinaemia centres around the use of a dopamine agonist, of which bromocriptine and cabergoline are the most widely used. Of course, if the hyperprolactinaemia is drug induced, stopping the relevant preparation should be commended. This may not, however, be appropriate if the cause is a psychotropic medication, for example a phenothiazine being used to treat schizophrenia. In these cases, careful discussion is required on appropriate fertility management with the patient’s psychiatrist.
Most patients show a fall in prolactin levels within a few days of commencing bromocriptine therapy and a reduction of tumour volume within six weeks. Side effects can be troublesome (nausea, vomiting, headache, postural hypotension) and are minimized by commencing the therapy at night for the first three days of treatment and taking the tablets in the middle of a mouthful of food. The longer-acting preparation cabergoline appears to have fewer side effects and is more commonly used these days. Indeed not only does cabergoline appear to be better tolerated and more efficacious than bromocriptine but it is also now the drug of choice for hyperprolactinemia. It is not licensed for women who wish to conceive and so the recommendation has been to switch to bromocriptine if fertility is desired, although there is some debate as to whether this is still appropriate advice [6].
Longer-term side effects include Raynaud’s phenomenon, constipation and psychiatric changes – especially aggression, which can occur at the start of treatment. Bromocriptine and cabergoline have been associated with pulmonary, retroperitoneal and pericardial fibrotic reactions and so echocardiography is recommended before starting treatment in order to exclude valvulopathy and this should be repeated after 3–6 months and then annually – although young patients are less at risk than older patients who may be prescribed higher doses for the management of Parkinson’s disease. The maintenance dose should be the lowest that reduces prolactin to normal levels and is often lower than that needed initially to initiate a response.
Surgery, in the form of a transsphenoidal adenectomy, is reserved for cases of drug resistance and failure to shrink a macroadenoma or if there are intolerable side effects of the drugs (the most common indication). Nonfunctioning tumours should be removed surgically and are usually detected by a combination of imaging and a serum prolactin concentration of < 3000 mIU/L. When the prolactin level is between 3000 and 8000 mIU/L, a trial of bromocriptine is warranted, and if the prolactin level falls it can be assumed that the tumour is a prolactin-secreting macroadenoma (Figure 15.1a). Operative treatment is also required if there is suprasellar extension of the tumour that has not regressed during treatment with bromocriptine and a pregnancy is desired. With the present-day skills of neurosurgeons in transsphenoidal surgery, it is seldom necessary to resort to pituitary irradiation, which offers no advantages and requires long-term surveillance to detect consequent hypopituitarism (which is immediately apparent if it occurs after surgery).
(a) Pituitary microadenoma: Cranial magnetic resonance imaging (MRI). A coronal section T1-weighted spin echo sequence after i.v. gadolinium. The normal pituitary gland is hyperintense (bright) while the tumour is seen as a 4 mm area of non-enhancement (grey) in the right lobe of the pituitary, encroaching up to the right cavernous sinus. It is eroding the right side of the sella floor (arrow). Pituitary macroadenoma: MRI scans of a pituitary macroadenoma before and after bromocriptine therapy.
(b) T1-weighted image post gadolinium enhancement demonstrating a macroadenoma with a large central cystic component (large arrow). There is suprasellar extension with compression of the optic chiasm (small arrows).
(c) After therapy the tumour has almost completely resolved and there is tethering of the optic chiasm (arrow) to the floor of the sella.
(d) Craniopharyngioma: Cranial MRI. Coronal T1-weighted section after gadolinium enhancement. The tumour signal intensity on the T1 image and only part of the periphery of the tumour enhances. The carotid arteries have a low signal intensity (black arrows) due to the rapid flow within them and are deviated laterally and superiorly by the mass (C), which arises out of the pituitary fossa (P).
Women with a microprolactinoma who wish to conceive can be reassured that they may stop bromocriptine when pregnancy is diagnosed and require no further monitoring, as the likelihood of significant tumour expansion is very small (less than 2%). On the other hand, if a patient with a macroprolactinoma is not treated with bromocriptine, the tumour has a 25% risk of expanding during pregnancy. This risk is probably also present if the tumour has been treated but has not shrunk, as assessed by CT or MRI scan (Figure 15.1b, c & d). The first-line approach to treatment of macroprolactinomas is therefore with bromocriptine combined with barrier methods of contraception. In cases with suprasellar expansion, a follow-up CT (or MRI) scan should be performed after three months of treatment to ensure tumour regression before it is safe to embark upon pregnancy. Bromocriptine can be discontinued during pregnancy, although an MRI scan should be performed if symptoms suggestive of tumour re-expansion occur, and it is necessary to recommence bromocriptine therapy if there is continuing suprasellar expansion. These patients also require expert assessment of their visual fields during pregnancy.
4 Polycystic Ovary Syndrome (WHO Group II)
PCOS accounts for approximately 80–90% of women with anovulatory infertility, which in turn comprises about a third of those attending the infertility clinic. A number of guidelines have been written for the management of anovulatory PCOS [7,8], the most recent by the World Health Organisation.
Various factors influence ovarian function and fertility, the most important being obesity. A patient’s weight correlates with both an increased rate of cycle disturbance and infertility secondary to disturbances in insulin metabolism. Monitoring treatment is also harder in obese women because their ovaries are more difficult to see on ultrasound scans, thus raising the risk of missing multiple ovulation and multiple pregnancy. Hypersecretion of LH is found in 40% of women with PCOS and is associated with a reduced chance of conception and an increased risk of miscarriage, possibly through an adverse effect of LH on oocyte maturation. Elevated LH concentrations are more often found in slim women with PCOS, whilst those who are overweight are more likely to be hyperinsulinemic.
4.1 Obesity and Lifestyle
Obesity worsens both symptomatology and the endocrine profile and so obese women (BMI > 30 kg/m2) should be encouraged to lose weight, by a combination of calorie restriction and exercise. Weight loss improves the endocrine profile and the likelihood of ovulation and of a healthy pregnancy. There is no evidence that women with PCOS benefit from a specific diet compared with obese women without PCOS [9]. The right diet for an individual is one that is practical, sustainable and compatible with her lifestyle. It is sensible to reduce glycemic load by lowering sugar content in favour of more complex carbohydrates and to avoid fatty foods. Meal replacement therapy or low calorie diets may be appropriate: it is often helpful to refer to a dietitian, if available. An increase in physical activity is essential, preferably as part of the daily routine. Thirty minutes per day of brisk exercise is encouraged to maintain health, but to lose weight, or sustain weight loss, 60 to 90 minutes per day is advised. Concurrent behavioural therapy improves the chances of success of any method of weight loss. There are no medications that have been shown to assist with long-term weight reduction. Bariatric surgery is used increasingly because of the global epidemic of obesity and certainly has a role in the management of obese women with PCOS [10]. It is recommended by some that anyone with a BMI of greater than 40 kg/m2 should be referred for consideration of bariatric surgery. If there are comorbidities, such as Type 2 diabetes (DM2), then the BMI cut-off for surgery is lower at 30–35 kg/m2.
4.2 Ovulation Induction Therapies
Strategies to induce ovulation include weight loss, oral anti-oestrogens (principally clomifene citrate), parenteral gonadotrophin therapy and laparoscopic ovarian surgery. There have been no adequately powered randomized studies to determine which of these therapies provides the best overall chance of an ongoing pregnancy when used as first-line therapy. Women with PCOS are at risk of OHSS and so ovulation induction has to be carefully monitored with serial ultrasound scans. The realization of an association between hyperinsulinemia and PCOS has resulted in the use of insulin-sensitizing agents such as metformin, although results have been disappointing.
Carefully conducted and monitored ovulation induction can achieve good cumulative conception rates, and, furthermore, multiple pregnancy rates can be minimized with strict adherence to criteria that limit the number of follicles that are permitted to ovulate.
4.3 Clomifene Citrate Therapy
The anti-oestrogen clomifene citrate (CC) has traditionally been used as first-line therapy for anovulatory PCOS [7–8,11]. Clomifene citrate therapy is usually commenced on day 2 of the cycle and given for five days. If the patient has oligo/amenorrhea, it is necessary to exclude pregnancy and then induce a withdrawal bleed with a short course of a progestogen, such as medroxyprogesterone acetate 20 mg/day for 5 to 10 days. The starting dose of CC is 50 mg/day, for 5 days beginning on days 3–5 of the menstrual cycle (the first day of bleeding is considered day 1 of the cycle). If the patient has not menstruated by day 35 and she is not pregnant, a progestogen-induced withdrawal bleed should be initiated. The dose of CC may be increased to 100 mg if there is no response. Doses of 150 mg/day or more appear not to be of benefit. If there is an exuberant response to 50 mg/day, as in some women with PCOS, the dose can be decreased to 25 mg/day. Discontinuation of CC therapy should be considered if the patient is anovulatory after the dose has been increased up to 100 mg/day. If the patient is ovulating, conception is expected to occur at a rate determined by factors such as the patient’s age. Clomifene citrate induces ovulation in approximately 70–85% of patients and approximately 60–70% should be pregnant by six cycles of therapy.
Clomifene citrate may cause an exaggeration in the hypersecretion of LH and have anti-oestrogenic effects on the endometrium and cervical mucus. We suggest measuring LH on day 8 of the cycle and if persistently elevated then move on to alternative therapy as the chance of conception is reduced and the risk of miscarriage increased [12,13]. All women who are prescribed CC should be carefully monitored with a combination of endocrine and ultrasonographic assessment of follicular growth and ovulation because of the risk of multiple pregnancies, which is approximately 10%. Clomifene therapy should therefore be prescribed and managed by specialists in reproductive medicine.
If pregnancy has not occurred after 6–9 normal ovulatory cycles, it is then reasonable to offer the couple assisted conception (that is in vitro fertilization (IVF)). Patients with anovulatory infertility who are resistant to anti-oestrogens may be prescribed parenteral gonadotrophin therapy or treated with laparoscopic ovarian surgery. The term ‘clomifene-resistance’, strictly speaking, refers to a failure to ovulate rather than failure to conceive despite ovulation, which should be termed ‘clomifene-failure’.
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