Ovulation induction

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CHAPTER 17 Ovulation induction

Maria Vogiatzi, Robert W. Shaw

Chapter Contents

INTRODUCTION 231
PRINCIPLES OF OVULATION 231
OVULATION DISORDERS 232
DIAGNOSIS AND TREATMENT 234
MEDICAL INDUCTION OF OVULATION 236
ANTIOESTROGENS 236
DOPAMINE AGONISTS 238
INSULIN-SENSITIZING AGENTS 239
PULSATILE GONADOTROPHIN-RELEASING HORMONE 239
GONADOTROPHINS 240
WEIGHT REDUCTION 242
SURGICAL MANAGEMENT: LAPAROSCOPIC OVARIAN DRILLING 243
RISKS OF INDUCTION OF OVULATION 244
CONCLUSIONS 248
KEY POINTS 248

Introduction

The aim of ovulation induction is to achieve development of a single follicle and subsequent ovulation in anovulatory infertile women. The ability to induce ovulation is possible in most women, with excellent conception rates. Anovulation accounts for 20–25% of the causes of infertility, and clinicians who manage infertile couples ought to have a sound understanding of the control of follicular development in a normal cycle (see Chapter 15), causes of anovulation (see Chapter 16), appropriate investigations and different treatment options, including their indications and risks. This chapter will briefly review the physiology of ovulation, including the basic principles of ovulation induction, and describe treatment strategies based on the underlying cause of the anovulation.

Principles of Ovulation

The ovary has two main functions: the cyclic release of haploid oocytes for fertilization by spermatozoa, and the production of steroid hormones (mainly oestrogen and progesterone). Both activities occur from puberty, when full sexual maturation has taken place, until the menopause, controlled by a sequence of hypothalamic–pituitary–ovarian interactions which, in turn, are synchronized by the endocrine, paracrine and autocrine secretory products of the ovary.

Follicular development: recruitment, selection and dominance

The primordial follicle constitutes the fundamental functional unit of the ovary. The primordial follicles contain oocytes that enter meiosis and are arrested in the diplotene stage of meiotic prophase to become primary oocytes. They can stay in this arrested phase for up to 50 years. Regular recruitment of primordial follicles occurs from puberty. The following stages of follicular development have been identified en route to ovulation: first, the primordial follicle becomes a primary or preantral follicle, then a secondary or antral follicle and finally a preovulatory follicle. The duration of each stage varies, with the primary to preantral stage being the longest and the preovulatory stage being the shortest.

In humans, approximately 15–20 early antral follicles are recruited for development at the start of each menstrual cycle. Of these 15–20 follicles, one usually emerges as dominant and is competent to ovulate. It takes approximately 85 days for a primordial follicle to reach the preovulatory stage. This follicular growth and development is regulated by gonadotrophins, and it is acknowledged that a lack of gonadotrophins leads to apoptotic death of the oocyte with subsequent accumulation of leukocytes and macrophages, as well as formation of fibrous scar tissue. This process is called ‘atresia’.

The follicle destined to ovulate is recruited from these preantral follicles in the first days of the menstrual cycle. An increase in follicle-stimulating hormone (FSH) is the critical feature in rescuing a cohort of follicles from atresia, eventually allowing a dominant follicle to emerge and proceed to ovulation. Maintenance of this increase in FSH for a critical duration of time over 4–6 days is essential.

The first signs of follicular development consist of an increase in the size of the oocyte and a change in the shape of the granulosa cells as they become more cuboidal. Small gap junctions also appear between the oocyte and the granulosa cells. The stromal cells differentiate into two layers: the theca interna and the theca externa. The granulosa layer is separated from the stromal cells by a basement membrane called the ‘basal lamina’.

As the oocyte enlarges, it enters the preantral stage. During this phase, there is further granulosa cell proliferation and growth. This is initiated by FSH. FSH also induces steroidogenesis in the granulosa cells and, in particular, oestrogen production. The oocyte is surrounded by a membrane called the ‘zona pellucida’. Under the synergistic effect of oestrogen and FSH, there is an increase in the production of follicular fluid. This leads to the formation of a cavity, called the ‘antrum’, and the follicle is now described as the antral follicle. The granulosa cells form the cumulus oophorus.

Only the cells of the theca interna possess receptors for luteinizing hormone (LH), whereas the granulosa cells bind FSH. Under the influence of gonadotrophins, the antral follicles produce steroids. The main oestrogens produced are oestradiol-17β and oestrone. In addition to this, antral follicles produce 30–70% of the circulating androgens, mainly androstenedione and testosterone. In particular, it is the thecal cells that produce androgens from acetate and cholesterol, and this action is stimulated by LH. On the other hand, the granulosa cells cannot produce androgens, but aromatize them to oestrogens; this process of aromatization is stimulated by FSH.

Follicular growth starts with the regression of the corpus luteum at the end of the previous cycle. As the levels of steroid hormones and inhibin drop, their inhibitory effect on FSH is abolished and FSH levels rise. This increase starts approximately 2 days prior to menstruation. As the follicles grow, the production of oestradiol and inhibin increases and FSH levels subsequently fall. The dominant follicle will be selected from day 5–7 of the menstrual cycle. The selection of a single dominant follicle appears to be the result of two oestrogen actions: a positive influence of oestrogen on FSH action within the maturing follicle, and a negative feedback mechanism on FSH at the hypothalamic–pituitary level. This latter action leads to a decline in gonadotrophin levels and ultimately to atresia of the less-developed follicles. Local paracrine–autocrine factors are also involved in this process, such as tumour necrosis factor and anti-Müllerian hormone. The dominant follicle is not affected by this decline in FSH levels, as it is more sensitive to FSH. Provided that a critical exposure of FSH was initially sustained, the dominant follicle continues to grow. In turn, FSH induces the development of LH receptors on the granulosa cells. Thus, LH plays a crucial role in the late stages of follicular development (Figure 17.1).

image

Figure 17.1 Follicle-stimulating hormone (FSH) threshold and window.

As the dominant follicle grows, it produces oestradiol. This explains the significant rise in oestradiol levels observed in the late follicular phase. High levels of oestradiol exert a positive feedback effect on LH secretion and enhance the follicle’s sensitivity to FSH. LH enhances androgen production in the theca cells, which leads to further oestrogen secretion by the granulosa cells via the process of aromatization. At midcycle, oestradiol levels reach a peak; this induces the LH surge, resumption of meiosis in the oocyte, luteinization of the granulosa cells and synthesis of prostaglandins. The prostaglandins stimulate the release of proteolytic enzymes within the follicular wall, which lead to ovulation (release of oocyte) 34–36 h after the LH surge commences.

Ovulation Disorders

Assessing ovulation

The choice of treatment to induce ovulation depends on reaching the correct diagnosis of the cause of anovulation. A thorough medical history and physical examination are the preliminary steps, and further investigations should be undertaken as indicated. It is highly recommended that these investigations should be conducted in a specialist centre, where there is access to skilled ultrasonography, radiology and a specialist endocrine laboratory. These tests will help the clinician to diagnose the cause of anovulation and exclude any important underlying pathology. Thyroid disease, hyperprolactinaemia, pituitary and ovarian tumours, polycystic ovary syndrome (PCOS), adrenal disease, extremes of weight and eating disorders are all associated with ovulation dysfunction. Early diagnosis is essential, as treatment of the underlying cause is more likely to succeed and prevent any long-term health consequences.

Classification

Ovulation disorders can be classified according to the anatomical site where the hypothalamic–pituitary–ovarian axis is deficient. The World Health Organization (WHO) classifies ovulation disorders into three groups, as follows.

• Group I: hypothalamic–pituitary failure. This group includes women with hypothalamic amenorrhoea or hypogonadotrophic hypogonadism. This includes anovulation related to stress, exercise, weight loss, anorexia nervosa, Kallmann’s syndrome and isolated (idiopathic) gonadotrophin deficiency. It does not include women with hypothalamic or pituitary tumours. This group of women have low serum FSH, LH and oestrogen levels, but normal prolactin.
• Group II: hypothalamic–pituitary dysfunction. This group includes women with amenorrhoea or oligomenorrhoea, with or without hyperandrogenism. This group predominantly comprises women with PCOS. Characteristically, these women exhibit normal FSH, oestrogen and prolactin levels, and variable changes in serum LH and testosterone.
• Group III: ovarian failure. This category includes women with amenorrhoea and elevated serum FSH and LH.
• Hyperprolactinaemic anovulation is considered a separate entity.

History

The majority of women of reproductive age have regular cycles ranging from 25 to 35 days. Usually, the presence of such cycles indicates ovulation.

Nevertheless, irregular, erratic or infrequent menses are suggestive of anovulation. Therefore, a detailed menstrual history should be taken. Amenorrhoea (absence of menstruation for 6 months), oligomenorrhoea (menses occurring less frequently than 6 weeks) and polymenorrhoea (menses occurring more frequently than 21 days) are associated with anovulation.

In addition, galactorrhoea, hot flushes and symptoms suggestive of thyroid disease could indicate an underlying ovulation dysfunction.

A careful gynaecological, medical, surgical and family history should be elicited. In particular, other causes of infertility should be excluded. A previous history of pelvic inflammatory disease, use of an intrauterine device, previous ectopic pregnancy or previous pelvic surgery is suggestive of tubal/ovarian pathology. In addition to this, any previous fertility investigations and therapies should be noted, and the absence of a contributory male factor should be confirmed.

Physical examination

The height and weight of the woman are of particular importance. Any deviation from normal should be noted, as this could be directly related to the underlying cause of anovulation (e.g. obesity and PCOS, short stature and Turner’s syndrome etc.). A more sensitive indicator is the body mass index (BMI), which is calculated from weight in kg/height in m2. The range for BMI is as follows.

• Underweight: <18.5
• Normal: 18.5–24.9
• Overweight: 25.0–29.9
• Obesity: 30.0–39.9
• Extreme obesity: ≥40

A general physical examination should be performed. This will include examination of the thyroid gland, breasts, facial and body hair. A thorough gynaecological examination must also be undertaken.

Investigations

Assessing ovulation is one of the primary investigations of infertility. Nevertheless, other factors should be evaluated. As 30–40% of cases of infertility are due to a male factor, a semen analysis should be requested early in the course of the investigations. Moreover, the female partner should have a test to assess tubal patency, such as a hysterosalpingogram, a diagnostic laparoscopy and dye test, or a hystero-ultrasonography (hycosy).

A serum progesterone measurement is the simplest and most reliable test to evaluate ovulatory function. The measurement of serum progesterone level should be performed in the midluteal phase (i.e. 7 days before the expected onset of the next period). Typically, in a 28-day cycle, the test is conducted on the 21st day of the menstrual cycle. Nevertheless, in women with prolonged, irregular cycles, serum progesterone is measured later in the cycle (i.e. on day 28 of a 35-day cycle) and is repeated weekly thereafter until the next menstruation. A mistimed blood sample is the most common cause of an abnormal result; thus, the first day of the next menstrual cycle should be recorded, and the midluteal phase will be calculated based on that to evaluate whether the test was appropriately timed.

Serum progesterone levels above 30 nmol/l are suggestive of ovulation. Any abnormal result indicates the need for further hormonal investigations. These will include measurement of serum FSH, LH and prolactin and thyroid function tests. Serum FSH and LH should be performed on day 2–5 of the cycle to avoid confusion with the normal, midcycle surge. In amenorrhoeic women or women with very infrequent cycles, the measurement of gonadotrophins can be done at any time and their interpretation will be based on the timing of their next menstruation. Both prolactin and thyroid function tests can be done at any time during the cycle.

The normal reference value for prolactin may vary between different laboratories. Usually, levels above 600 mIU/ml are considered abnormal. Raised prolactin concentrations should be confirmed by a repeat measurement. The evaluation of hyperprolactinaemia should include pituitary/hypothalamic imaging, such as radiography, computed tomography or magnetic resonance imaging. The pituitary imaging is essential to exclude a prolactin-producing adenoma or an empty sella. Moreover, as primary hypothyroidism can lead to secondary hyperprolactinaemia, thyroid function tests are indicated in the presence of hyperprolactinaemia and a careful drug history to exclude a pharmacological cause.

In the presence of low gonadotrophin levels, pituitary/hypothalamic imaging is indicated in order to exclude a space-occupying lesion, as well as a full pituitary hormone secretion assessment.

In the case of PCOS, the hormonal investigations should include serum androgens (testosterone, free testosterone, androstenedione and dehydroepiandrosterone sulphate), as they are often elevated, and baseline 17OH-progesterone. Depending on the results, adrenocorticotrophic hormone concentrations may be measured to exclude adrenal pathology. If PCOS is suspected, a transvaginal ultrasound should be performed to assess the ovaries and look for the characteristic peripheral follicles (‘necklace sign’). The criteria used for the ultrasonographic diagnosis of PCOS include the presence of more than 10 follicles with a diameter of 2–10 mm and increased density of the ovarian stroma (Adams et al 1986).

If premature ovarian failure is diagnosed, further investigations should include chromosome analysis and autoantibody screening.

Basal body temperature (BBT) charts have also been used for assessing ovulation, as ovulatory cycles have been associated with a classic biphasic BBT pattern. The woman is asked to record her temperature every morning, before getting out of bed. Usually, the temperature shows a rise after ovulation. Chaotic BBT recordings are suggestive of anovulation. Nevertheless, the BBT may not appear clearly biphasic in some patients with ovulatory cycles. Therefore, BBT charts are not considered reliable to predict ovulation, and their use is not recommended alone without serum progesterone measurements.

Diagnosis and Treatment

Based on the results of the above investigations, the causes of anovulation can be divided into four main categories (see Box 17.1).

Box 17.1 Classification of ovulation disorders

Intrinsic ovarian failure

• Genetic
• Autoimmune
• Others (e.g. chemotherapy and radiotherapy)

Secondary ovarian dysfunction

Disorders of gonadotrophin regulation

Specific

• Hyperprolactinaemia
• Kallmann’s syndrome (WHO Group I)

Functional (WHO Group II)

• Weight loss
• Exercise
• Drugs
• Idopathic

Gonadotrophin deficiency (WHO Group I)

• Pituitary tumour
• Pituitary necrosis or thrombosis

Disorders of gonadotrophin action (WHO Group II)

• Polycystic ovary syndrome

Hyperprolactinaemia

Causes of hyperprolactinaemia include:

• prolactin-producing adenomas (microadenomas <1 cm, macroadenomas >1 cm);
• any masses that apply pressure on the pituitary stalk and therefore block the inhibitory effect of the hypothalamus;
• primary hypothyroidism;
• drugs that inhibit central dopaminergic activity, such as oestrogen (combined oral contraceptive), dopamine receptor antagonists (metoclopramide, phenothiazines), opioids and dopamine-depleting agents (reserpine, methyldopa);
• chronic renal failure; and
• ectopic prolactin secretion by an extrapituitary tumour.

High levels of prolactin interfere with the pulsatile secretion of gonadotrophin-releasing hormone (GnRH) and subsequently impair normal ovarian function. Therefore, women with hyperprolactinaemia may present with menstrual irregularities, anovulation and galactorrhoea.

In the case of microprolactinomas, the mainstay of therapy is the administration of dopamine agonists, such as bromocriptine and cabergoline. Surgical treatment, in the form of trans-sphenoidal pituitary adenomectomy, is indicated for macroprolactinomas but is associated with risks including panhypopituitarism and cerebrospinal fluid leakage.

Non-prolactin-secreting tumours are treated surgically in combination with radiotherapy.

Primary hypothyroidism causing hyperprolactinaemia is treated with thyroid replacement therapy.

Hypergonadotrophic hypogonadism

Hypergonadotrophic hypogonadism or premature ovarian failure is defined as menopause occurring before the age of 40 years. It may be due to various causes:

• chromosomal abnormalities (e.g. mosaic Turner’s syndrome);
• autoimmune disease: autoantibodies are detected against ovarian cells, gonadotrophin receptors and/or the oocytes. Often, premature ovarian failure occurs in association with other autoimmune disorders, such as diabetes mellitus, hypothyroidism and Addison’s disease;
• infection (e.g. mumps oophoritis);
• previous surgery, radiotherapy or chemotherapy; or
• idiopathic.

The only treatment option for patients with premature ovarian failure is in-vitro fertilization (IVF) with donor eggs. In terms of their long-term management, they should be offered hormone replacement therapy to protect their skeleton and cardiovascular system from the effects of hypo-oestrogenism.

Hypogonadotrophic hypogonadism

Hypogonadotrophic hypogonadism is a state of gonadal dysfunction, characterized by hypo-oestrogenaemia, anovulation and amenorrhoea, due to anatomical and/or functional disorders of the hypothalamus/pituitary gland. In hypogonadotrophic hypogonadism, there is a deficient secretion of GnRH and/or FSH and LH. Patients present with primary or secondary amenorrhoea and infertility.

Its causes can be either congenital or acquired. Kallman’s syndrome is one of the congenital causes. It consists of isolated gonadotrophin deficiency and anosmia. The syndrome is usually sporadic but it can also be inherited (see Chapter 16).

Acquired causes of hypogonadotrophic hypogonadism include:

• central nervous system tumours, i.e. space-occupying lesions around the hypothalamus or the pituitary that disrupt gonadotrophin secretion. The most common of these tumours is craniopharyngioma;
• Sheehan’s syndrome, i.e. pituitary necrosis due to massive obstetric haemorrhage with hypovolaemic shock;
• postradiation hypothalamic dysfunction;
• isolated GnRH deficiency;
• inflammatory or infiltrative processes of the pituitary;
• pituitary infarction
• eating disorders (anorexia nervosa) with excessive weight loss;
• stress; and
• excessive exercise.

In patients with hypogonadotrophic hypogonadism, ovulation is restored with the administration of gonadotrophins. Pulsatile GnRH is only indicated in the presence of intact pituitary function.

If a central nervous system tumour is present, surgery is indicated.

Patients with anorexia nervosa may benefit from weight gain and psychotherapy. Nevertheless, in cases of persistent anovulation despite adequate weight gain, gonadotrophins or pulsatile GnRH can be considered.

image

Figure 17.2 Ultrasound appearances of a polycystic ovary: longitudinal and transverse views.

Normogonadotrophic hypogonadism

This category includes women with anovulation with normal FSH, LH and prolactin levels. They may present with regular menses, oligomenorrhoea or even amenorrhoea. Predominantly, this group comprises women with PCOS. This is discussed in more detail in Chapter 18.

Other causes of normogonadotrophic hypogonadism and hyperandrogenism include:

• late-onset congenital adrenal hyperplasia;
• adrenal tumours; and
• androgen-producing ovarian tumours (see Chapter 26).

In the presence of PCOS, obese patients will benefit from weight loss. This will not only improve their response to ovulation induction, but may also lead to resumption of spontaneous ovulation. The pharmacologic agent most commonly used for ovulation induction in women with PCOS is clomiphene citrate (CC). If patients fail to respond to it, gonadotrophins or insulin-sensitizing agents may also be used. Laparoscopic ovarian drilling has also been used for PCOS patients unresponsive to CC.

A summary of investigations, classifications and treatments is shown in Figure 17.3, and an overview of assessments and treatments is given in the guidelines of the National Institute for Health and Clinical Excellence (2004).

image

Figure 17.3 Flowchart of diagnosis and treatment. FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; GnRH, gondotrophin-releasing hormone.

Medical Induction of Ovulation

Effective use of drugs used to induce ovulation comes from an indepth understanding of their mechanism of action.

Antioestrogens

Non-steroidal selective oestrogen receptor modulators, including CC and tamoxifen, are used for ovulation induction. It is thought that they bind with oestrogen receptors in the hypothalamus, leading to a perceived drop in the endogenous oestrogen levels. As a consequence, GnRH and endogenous gonadotrophin secretion is increased, leading to induction of ovulation. Figure 17.4 shows the structure of the drugs.

image

Figure 17.4 Structure of oestradiol and antioestrogen derivatives used in ovulation induction.

Clomiphene citrate

CC is the most commonly used ovulation induction agent, and most evidence on the efficacy of antioestrogens derives from its use, since its introduction in 1962.

Pharmacology/mechanism of action

CC is a non-steroidal triphenylethylene derivative with both oestrogenic and antioestrogenic properties; nevertheless, it mainly acts as an antioestrogen.

Indications for treatment

CC is the drug of choice for anovulatory infertile women with WHO Group II ovulation disorder, that is women with oligo- or amenorrhoea, with or without hyperandrogenism, and normal levels of prolactin, oestrogen and thyroid hormones. Typically, this group includes women with PCOS.

CC has also been tried for the treatment of unexplained infertility. Nonetheless, when CC treatment was compared with placebo or no treatment, there was no evidence that CC was more effective in this subgroup of infertile women (Hughes et al 2000).

Treatment regimens and monitoring

CC treatment is typically started with a daily dose of 50 mg, from day 2 of the cycle, for a total of 5 days. For amenorrhoeic women, treatment can be commenced at any time, provided pregnancy has been excluded or following a progestogen challenge test. Different regimens have also been tried, and overall CC treatment can safely be initiated anywhere between days 2 and 5 of the cycle for a total period of 5 days. Ovulation usually occurs 5–10 days after the course of treatment has been completed.

If ovulation is not induced with the initial dose of 50 mg, the dose of CC can be increased in 50-mg increments in subsequent cycles up to a maximum dose of 250 mg/day. Approximately 70% of anovulatory women treated with CC respond to a dose of 100–150 mg/day (Gysler et al 1982). In practice, doses of 250 mg are rarely used. Women who do not ovulate while taking a dose of 150 mg are considered to be ‘clomiphene-resistant’ (Vandermolen et al 2001). The required CC dose is correlated to body weight, as there is a significant association between CC treatment failure and BMI greater than 27 kg/m2. Women who are overweight should be advised that a 5% reduction in weight may improve endocrine and ovarian function, increase spontaneous conception rates and improve the response to CC treatment. Lower doses of 25–50 mg/day should be considered for those women who are exceptionally sensitive to treatment with CC.

Monitoring of CC treatment is recommended. Ovulation is confirmed either with serum progesterone measurements or with the use of transvaginal ultrasonography. Serum progesterone concentrations are measured during the luteal phase. Ultrasound monitoring should be offered at least during the first treatment cycle to ensure that the woman is on the lowest necessary dose to achieve ovulation (National Institure for Health and Clinical Excellence 2004). Monitoring will minimize the risk of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS), and is essential in patients in whom ovulation does not seem to have been induced.

Results

Studies with CC have shown an ovulation rate of 60–85% and a pregnancy rate of 30–40%. The discrepancy between ovulation and fecundity rates has not been explained, but may be due to other coexisting fertility factors, such as endometriosis or tubal damage. Some argue that it may be associated with possible antioestrogenic effects that CC exhibits on the endometrium and cervical mucus (Milson et al 2002).

A systematic review of 12 randomized controlled trials supported the effectiveness of CC therapy for anovulatory infertile women (Beck et al 2005). Clomiphene was found to be effective in increasing pregnancy rate compared with placebo [fixed odds ratio (OR) 5.8, 95% confidence interval (CI) 1.6–21.5; number needed to treat (NNT) 5.9, 95% CI 3.6–16.7].

Cumulative conception rates continue to rise after six cycles of treatment, reaching a plateau after 12 cycles. However, prolonged treatment with CC may be associated with an increased risk of ovarian malignancy. Therefore, after completion of 12 cycles of treatment, alternative therapies ought to be considered (National Institute for Health and Clinical Excellence 2004). Factors associated with increased risk of CC treatment failure include increased maternal age, raised BMI and history of severe oligomenorrhoea (Milson et al 2002).

Side-effects

Side-effects with CC treatment are common, but usually mild and transient. Hot flushes and other vasomotor symptoms may occur in up to 10% of patients. Other symptoms include abdominal pain, nausea, vomiting, breast tenderness, headache, insomnia and hair loss. Rarely, visual disturbances (scotomata, blurred or doubled vision) may occur. In the latter case, CC should be discontinued and ophthalmology assessment arranged if symptoms do not cease.

Risks of treatment

With CC therapy, the risk of multiple gestation is approximately 2–13% (Venn and Lumley 1994). OHSS may occur in approximately 13% of cases, whereas severe OHSS is rare. Counselling of women undergoing ovulation induction with CC regarding the above risks is, therefore, essential.

The incidence of spontaneous miscarriage is 13–25% (Milson et al 2002). This figure is no different from the incidence of miscarriage in spontaneous conceptions. In addition to this, there is no evidence to indicate that CC treatment is associated with a higher incidence of congenital abnormalities.

Adjuvant treatment

A systematic review of 12 randomized controlled trials (Beck et al 2005) examined the concomitant administration of CC with other agents to infertile anovulatory women. The use of clomiphene in combination with tamoxifen did not provide any evidence of increased effect on pregnancy rate compared with clomiphene alone. The results were similar when CC plus ketoconazole was compared with CC alone, and CC plus bromocriptine was compared with CC alone.

However, clomiphene plus dexamethasone treatment resulted in a significant improvement in pregnancy rate (fixed OR 11.3, 95% CI 5.3–24.0; NNT 2.7, 95% CI 2.1–3.6) compared with clomiphene alone, as did clomiphene plus pretreatment with combined oral contraceptives (fixed OR 27.2, 95% CI 3.1–235.0; NNT 2.0, 95% CI 1.4–3.4).

Tamoxifen

Tamoxifen is a triphenylethylene derivative structurally similar to CC. It has been widely used in the treatment of breast cancer. In ovulation induction, tamoxifen is administered in doses of 20–80 mg/day, from day 2 to day 6 of the cycle. Tamoxifen, unlike CC, does not exhibit any antioestrogenic effects on the endometrium or vaginal mucosa. Therefore, it was thought that its use might be superior to CC.

Preliminary research has shown that tamoxifen has similar ovulation (44% with tamoxifen vs 45% with CC) and pregnancy rates (22% with tamoxifen vs 15% with CC) (Boostanfar 2001, Gerhard and Runnebaum 1979) compared with CC.

A meta-analysis, involving four trials, compared tamoxifen with CC in anovulatory women and showed that the two drugs were equally effective. Both drugs resulted in similar ovulation rates (OR 0.755, 95% CI 0.513–1.111). No benefit of tamoxifen over CC in achievement of pregnancy per cycle (OR 1.056, 95% CI 0.583–1.912) or per ovulatory cycle (OR 1.162, 95% CI 0.632–2.134) was demonstrated (Steiner et al 2005).

One randomized controlled trial showed that combination therapy of tamoxifen with CC did not improve pregnancy rates [8.6% with tamoxifen/CC vs 4.8% with CC alone; relative risk (RR) 1.80, 95% CI 0.20–16.21] (Suginami 1993).

In most units, tamoxifen is utilized as a second-line therapy in patients who experience side-effects on CC or who appear non-responsive.

Letrozole

Letrozole, an aromatase inhibitor, may be an alternative option for clomiphene-resistant anovulatory women. It has even been suggested that letrozole could be used as a first-line ovulation induction agent instead of CC. However, experience with this medication remains limited, and further research is needed to establish its role, utility and safety.

Pharmacology and mechanism of action

Aromatase inhibitors were initially introduced for the treatment of breast cancer. Aromatase is a cytochrome P-450 haemoprotein that catalyses the rate-limiting step in the production of oestrogens using androgens as a substrate. Letrozole is a highly potent, selective and reversible aromatase inhibitor (Bayar et al 2006). Letrozole inhibits peripheral oestrogen production and, therefore, stimulates endogenous FSH secretion. Moreover, the accumulated androgens may increase follicular sensitivity to FSH (Mitwally and Casper 2004). Its high oral bioavailability and short half-life make it a suitable agent for ovulation induction. One potential advantage of letrozole over CC is its lack of direct antioestrogenic effects on the cervical mucus, the endometrium, uterine blood flow and embryo development (Barroso et al 2006).

Results

In a Cochrane review, Cantineau et al (2007) identified five trials comparing aromatase inhibitors with antioestrogens used as ovulation induction agents in ovarian stimulation protocols for intrauterine insemination (IUI) in subfertile women. No benefits of letrozole use were identified. Other studies involving women with anovulation or unexplained infertility have shown comparable pregnancy rates between letrozole and CC (Barroso et al 2006, Bayar et al 2006, Davar et al 2006, Jee et al 2006). One study reported higher pregnancy rates in PCOS patients treated with letrozole (Atay et al 2006). Results from larger randomized controlled trials are needed to determine the role of letrozole in ovulation induction.

Dopamine Agonists

Pharmacology and mechanism of action

Prolactin secretion from the anterior pituitary is mainly regulated by the inhibitory control of dopamine. Therefore, drugs that exhibit a dopaminomimetic activity reduce prolactin serum concentrations and restore gonadal function in hyperprolactinaemic women, with or without a pituitary adenoma. If a prolactinoma is present, dopamine agonists may also reduce tumour size (see Chapter 16).

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