Clomiphene citrate (clomiphene)

Clomiphene (), a triphenylethylene derivative, was synthesized in 1956 and introduced for clinical trials in 1960; it is a mixture of two isomers, zuclomiphene and enclomiphene (). Zuclomiphene appears to be the important isomer for ovulation induction.

Clomiphene acts both as an oestrogen agonist and an antioestrogen. An antihormone is a compound which binds to specific hormone receptors but which does not cause stimulation of intracellular events in the way in which the relevant hormone would, but which instead blocks the action of that hormone. Clomiphene has been shown to occupy oestrogen receptors for a prolonged period of time. In one study clomiphene or its metabolites were found in the circulation for 1 or 2 weeks or more after the last dose in some women (). It acts at hypothalamic-pituitary level as well as on oestrogen receptors in other tissues; it causes an increase in LH and FSH levels in association with an increase in pulse frequency ().

Indications

Clomiphene has been used in clinical practice for about 30 years, mainly to stimulate follicular development. Some of the indications for its use in the management of subfertility are shown in Table Some indications for the use of clomiphene citrate in the management of subfertility:

  • Hypothalamic (eugonadotrophic euprolactinaemic) amenorrhoea
  • Long cycles
  • Polycystic ovary syndrome
  • Luteal phase defect
  • Assisted conception programmes

The usual starting dose is 50mg/day for 5 days from the third day of the cycle but it is modified depending on the clinical situation (). If the dose is adequate ovulation will usually occur 5-10 days after the last clomiphene tablet is taken. If pregnancy does not ensue, a period will occur approximately 14 days after ovulation and treatment can be recommenced from the third day of the cycle.

Hypothalamic amenorrhoea

Normal weight amenorrhoeic women, with normal prolactin and gonadotrophin levels, respond very well to clomiphene if their oestrogen levels are adequate. Clomiphene 50mg/day (increased, if no response, to 100mg/day) should be given for 5 days and repeated from the third day of the cycle if a period occurs. Human chorionic gonadotrophin (hCG) can be administered if adequate follicular development is not followed by ovulation ().

Long cycles

Clomiphene 50mg/day for 3 or 5 days from the third day of the cycle will often reduce the cycle length to normal and thus achieve more frequent ovulation than was occurring with a long cycle.

Polycystic ovary syndrome

Clomiphene is the initial treatment of choice in this condition. It is wise to start with a low dose of clomiphene (25 mg or 50 mg/day for 5 days from the third day of the cycle) in these patients to reduce the likelihood of hyperstimulation.

Luteal phase defect

The diagnosis and management of this condition are controversial (). Treatment with clomiphene has been found to be beneficial; alternatively treatment with progesterone may be used (), or gonadotrophin therapy may be instituted.

Follicular stimulation for assisted conception

Clomiphene is used in combination with human menopausal gonadotrophin for follicular stimulation in some assisted conception programmes.

Monitoring therapy with clomiphene

The simplest and cheapest way to monitor ovulation induction with clomiphene is with a basal body temperature chart. This will give an indication of whether ovulation is occurring and of the length of the luteal phase in most patients (). If the temperature chart does not show a clear biphasic pattern the plasma progesterone level should be measured a week before a period is expected. It should be >30 nmol/19 to 5 days before a period. If it is not elevated at the appropriate time, evidence of follicular development in response to clomiphene administration should be sought, either by measuring oestradiol levels twice, on day 1 to 5 and again on day 14 to 16, or by ultrasound assessment of follicular growth. Plasma oestradiol levels should increase from approximately 100-200, to 500-1500pmol/1 or more (). If there is either an increase in oestradiol levels indicative of follicular development, or development of a follicle to 18-20 mm, hCG 5000 or 10000 units should be given 7-10 days after the last dose of clomiphene or when the follicle reaches 18-20 mm. If it is effective (as determined by temperature chart or by progesterone estimation 1 week after hCG administration), it should be given in subsequent cycles.

If there is no evidence of follicular growth the dose of clomiphene should be increased from 50mg/day to 100mg/day, and if necessary up to 150mg/day, for 5 days from the third day of the cycle. If follicular development still does not occur, the choice is to increase further the dose or duration of clomiphene () or to change to treatment with either hMG or LHRH infusion, or in the case of women with polycystic ovaries to consider laparoscopic ovarian diathermy (), or the addition of prednisone or of dexamethasone ().

Results

In one study of 428 women it was found that more than 95% of pregnancies that followed treatment with clomiphene occurred in the first six ovulatory cycles () and that the majority of conceptions occurred with a dose of 50 mg. The ovulation and pregnancy rates depend on the underlying cause of anovulation and are reduced in women with the polycystic ovary syndrome. Overall more than 80% of well-selected patients can be expected to ovulate following treatment with clomiphene and at least 60-80% of these to conceive ().

Side-effects

The most common side-effects are discomfort due to ovarian enlargement, hot flushes and an increased incidence of twin pregnancy. Visual symptoms, such as blurring, spots or flashes, are less common but are an indication for stopping treatment. Ovarian enlargement occurred in 13.9% and hot flushes in 10.7% of patients in a series of more than 6000 anovulatory women treated with clomiphene in a number of different dose regimens, but ovarian enlargement occurred in only 7% of patients treated with doses of clomiphene of 50 and 100 mg (). Massive ovarian enlargement is uncommon with clomiphene treatment () but it can occur unexpectedly, particularly in women with polycystic ovaries, and it also occurred in a woman who was later found to be profoundly hypothyroid ().

In a series of 2369 pregnancies the incidence of multiple pregnancy following spontaneous conception was increased to approximately 8% in women treated with clomiphene; fortunately most of these were twin pregnancies and a higher multiple pregnancy occurred in less than 1% (0.5% triplets, 0.3% quadruplets, 0.13% quintuplets) of these pregnancies (). Clearly there is a much increased rate of multiple pregnancy following assisted conception.

It used to be thought that the miscarriage rate was increased in women treated with clomiphene but it is probably no greater than in a similar group of infertile women; likewise it appears that the fetal abnormality rate is no higher than in an appropriate control population ().

Tamoxifen citrate (tamoxifen)

Tamoxifen is another antioestrogen which can be used for ovulation induction and for treatment of a luteal phase defect () in the same way as clomiphene, starting with a dose of 10 or 20mg/day for 5 days from the third day of the cycle. However, it is mainly used in the treatment of breast cancer, for which clomiphene is not appropriate because of its toxicity when used for a prolonged period of time.

Human menopausal gonadotrophin (hMG)

Serum gonadotrophins from pregnant mares were used in the 1940s to stimulate follicular development but because of antigenicity this form of treatment was abandoned. The use of human pituitary gonadotrophins for the induction of ovulation in amenorrhoeic women was first reported by Gemzell in 1958 (). Gonadotrophins derived from human pituitary glands were prohibitively expensive and gonadotrophins were subsequently purified from menopausal urine and introduced for the induction of ovulation in the early 1960s. Urinary FSH has a lower molecular weight and reduced biological activity compared to pituitary FSH but when comparable doses are given the clinical effects are indistinguishable. Human menopausal gonadotrophin (hMG) is marketed in ampoules containing 75 iu FSH and 75 iu LH (Pergonal). Recently pure FSH has been prepared from hMG by immunochromatography; it is marketed in ampoules containing 75 iu FSH, with less than liu LH (Metrodin).

Indications

Human menopausal gonadotrophin is used in the treatment of euprolactinaemic anovulatory infertility, refractory to treatment with antioestrogens, and to induce multiple follicular development in assisted conception programmes. It should only be given when adequate monitoring facilities are available because of the increased likelihood of hyperstimulation and multiple gestation with this form of treatment. Patients must be made fully aware of the significance of these possible complications and should sign an appropriately worded consent form before treatment is started.

Follicular development is stimulated by the administration of hMG on a daily or alternate day basis but the response varies from one woman to another and the treatment needs to be individualized. Polycystic ovaries are particularly sensitive to stimulation with gonadotrophins and extra caution is required in treating women with the polycystic ovary syndrome with hMG.

Several regimens have been described and a flexible approach is necessary. One or two ampoules of Pergonal are given daily or on alternate days until plasma oestradiol levels reach approximately 2000-3000 pmol/1 or the leading follicle measures 16-18 mm in diameter. If there is no response by day 5, the dose of Pergonal is increased. If there is still no response after 2 more days, the dose is increased again. Once oestradiol levels begin to rise the daily dose of Pergonal is kept constant until the leading follicle measures 16-18 mm in diameter (follicular growth normally occurs at a rate of approximately 2 mm/24 hours). Treatment with hMG is then discontinued and, provided that neither the number of preovulatory follicles nor the plasma oestradiol level are excessive, hCG (5000-10000 units) is given. The couple are advised to have intercourse on the day of hCG adminstration and on the next 2 days.

A spontaneous LH surge does not usually occur with hMG therapy and so there is fortunately some control over whether ovulation does or does not occur in a particular cycle. Ultrasound and oestrogen assays are of value in the prevention of hyperstimulation, as the incidence is increased when there is an excessive number of small and intermediate follicles, which may continue to develop, and when oestradiol levels are particularly high. Hyperstimulation is unlikely to occur if hCG is withheld, as it does not occur in the absence of ovulation. Thus with adequate ultrasound and oestrogen monitoring the likelihood of multiple pregnancy and of hyperstimulation can be reduced ().

Ovarian hyperstimulation

Various systems of classification have been proposed (). A simple classification is into mild, moderate or severe hyperstimulation ().

Symptoms of hyperstimulation begin 3-7 days after hCG administration and usually regress after a few days in the absence of pregnancy; severe hyperstimulation occurs most commonly in conception cycles. It occasionally occurs following treatment with clomiphene or pulsatile LHRH but is most often associated with gonadotrophin therapy.

Severe ovarian hyperstimulation is a life-threatening condition and several deaths have been reported. The ovaries are usually larger than 10cm in diameter and there is marked ascites with gross abdominal distension. Pleural effusions may occur. The fluid shift from the circulation is due to increased capillary permeability. It leads to hypovolaemia and haemoconcentration with electrolyte imbalance, which may progress rapidly to oliguria and hypovolaemic shock. Coagulation disorders and thromboembolic episodes may occur.

Various theories have been postulated to explain the features of severe ovarian hyperstimulation, including a direct action of oestrogen or other hormones, histamine release, increased prostaglandin production and, most recently, increased ovarian production of prorenin.

It appears that the likelihood of ovarian hyperstimulation is reduced in assisted conception cycles when as many follicles as possible are aspirated, but this does not completely prevent the occurrence of hyperstimulation.

Management of ovarian hyperstimulation

Women with mild ovarian hyperstimulation should be advised to rest, and not to have intercourse which might lead to rupture of a cystic follicle, and to report any deterioration in their symptoms. Those with moderate or severe hyperstimulation should be admitted to hospital. They should be weighed and baseline plasma haematological and biochemical, and urinary (including osmolality) investigations should be performed, as well as ultrasound assessment of the ovaries and of the amount of ascitic fluid.

The main problem is the loss of fluid from the circulation and this should be corrected by the administration of a plasma expander or, in the presence of hypoalbuminaemia, plasma or albumin. An accurate fluid balance chart must be kept.

Surgery is indicated only if torsion or rupture of an ovarian cyst occurs or if there is intraperitoneal haemorrhage. Successful non-surgical management of a woman with an ectopic pregnancy and severe ovarian hyperstimulation has been reported using methotrexate ().

Paracentesis may be beneficial if ascites is pronounced (). It must be carried out under ultrasound control to avoid puncturing an ovarian cyst. Rarely it may be necessary to tap a pleural effusion.

Results

The majority of pregnancies that will occur with treatment with hMG, occur in the first 3-6 cycles. The success rate depends on the indication for treatment and is greatest in women with hypogonadotrophic hypogonadism. Ovulation rates vary from approximately 65% to 99%, conception rates from 25% to 72%, miscarriage rates from 12% to 30% and multiple pregnancy rates from 10% to 40%; the successful pregnancy rates are lower in women over 35 years of age than in younger women (). Most twin pregnancies that occur are dizygotic but there is also an increase in the incidence of monozygotic twins following gonadotrophin therapy.

Luteinizing hormone releasing hormone (LHRH)

LHRH is secreted in pulsatile fashion by the hypothalamus (). Induction of ovulation can be achieved in suitable subjects, particularly those with idiopathic hypogonadotrophic hypogonadism (hypothalamic amenorrhoea) who have failed to respond to treatment with clomiphene, by pulsatile administration of LHRH using a portable pump ().

One type of pump is designed to normally deliver a bolus of 15 µg LHRH in 100 µl solution every 90 minutes (). The same rate of administration of the pulses is maintained throughout the cycle; it does not need to be altered even though, in a spontaneous cycle, pulse frequency and amplitude are specific to the phase of the cycle.

Subcutaneous administration of LHRH is preferable to the intravenous route, because of the greater risk of infection with intravenous administration, but the intravenous route may be successful in women in whom there is an inadequate response to subcutaneous therapy. The common sites of needle insertion are the subcutaneous fat of the upper arm (distal to the humeral attachment of the deltoid), the lower abdominal wall and the anterolateral aspect of the thigh. The subcutaneous insertion site needs to be changed every 2 days.

A baseline scan is performed prior to commencing therapy to ensure that the ovaries are inactive and that the endometrium is thin; ultrasound monitoring of the ovaries and endometrium is performed during the treatment cycle, 1 week after starting treatment and then every 2 or 3 days. After the dominant follicle has reached a diameter of 12 mm it grows at a rate of approximately 2 mm/24 hours. The average maximum preovulatory diameter is 20-22 mm, but there is considerable variation between patients. A corpus luteum can be seen 24-48 hours after ovulation. Some groups have preferred to administer hCG for luteal phase support rather than to continue the LHRH infusion ().

Ovulation induction with pulsatile LHRH infusion is most successful in normal weight women with idiopathic hypogonadotrophic hypogonadism (hypothalamic amenorrhoea), with a cumulative pregnancy rate of 95% in 6 months in one study (). The rate of conception in this group is thus the same as that of a normal population. In women with the polycystic ovary syndrome the cumulative pregnancy rate was 74% in 6 months and there was an increased rate of miscarriage. Adverse features in this group were obesity, hyperandrogenism and high LH concentrations. Combined treatment with oral clomiphene and pulsatile LHRH is successful in some patients who are unresponsive to clomiphene or LHRH when given alone ().

The advantages of treatment with pulsatile LHRH infusion as opposed to hMG are that there is almost no danger of ovarian hyperstimulation and the incidence of multiple pregnancy is much less. If a multiple pregnancy does occur it is usually a twin rather than a higher multiple pregnancy, although triplet and quadruplet pregnancies have reported (). Twin pregnancies have been found to occur more commonly in the first than in subsequent treatment cycles ().

LHRH agonists

LHRH agonists provide a means of inducing reversible reduction of ovarian steroidogenesis. They cause an initial increase in gonadotrophin levels followed by a decrease while administration continues. Prolonged duration of action can be achieved by frequent administration with, for example, buserelin (Suprefact) nasal spray, or by using a depot injection, e.g. goserelin (Zoladex) implant. Some indications for their use are shown in Table Some indications for the use of LHRH agonists:

  • Endometriosis
  • Fibroids (especially prior to myomectomy)
  • Menorrhagia
  • Prior to ovulation induction therapy in some cases
  • Premenstrual syndrome
  • Precocious puberty

Treatment of endometriosis with LHRH agonists appears to be as effective as treatment with danazol, with less severe side-effects ().

LHRH agonist administration results in marked reduction in the size of fibroids in many cases but unfortunately the fibroids usually revert to their previous size when treatment is stopped (). It can, however, be useful prior to myomectomy as it reduces blood loss at operation. It can also be a useful temporary treatment in the management of severe menorrhagia, allowing time for the haemoglobin to rise and for the woman to decide whether she wishes to undergo surgical treatment.

Ovarian suppression is also indicated in the management of some women prior to ovulation induction with gonadotrophins and it has been used successfully in women with intractable premenstrual symptoms () and children with precocious puberty ().

Side-effects

Side-effects due to a reduction in oestradiol levels are common and include hot flushes and vaginal dryness. These are reversible on stopping treatment. Breakthrough bleeding may also occur. Long-term administration of LHRH agonists is currently contraindicated because prolonged low oestrogen levels result in abnormalities in bone metabolism similar to those which occur after the menopause. These changes appear, however, to be reversible within 6 months following a 6-month period of treatment. It is not known what effect longer periods of treatment would have or whether other drugs could be effectively given concurrently to prevent bone loss ().

 

Selections from the book: “Introduction to Clinical Reproductive Endocrinology”. Edited by Gillian C. L. Lachelin, 1991.

Share →