Ovulation induction is indicated for the treatment of anovulatory infertility, once pathological causes have been excluded.

Pharmacological induction of ovulation – clomiphene citrate (Clomid and Serophene)

■  Clomiphene citrate causes an increase in pituitary gonadotrophin release, stimulating maturation of the ovarian follicle.

■  It has a half-life of 5-7 days and there is a slow rate of clearance, so clomiphene levels will increase in serum over time following successive monthly treatment cycles.

■  It competes with endogenous circulating oestrogens for oestrogen-binding sites in the hypothalamus. It blocks normal negative feedback of the endogenous oestrogens and produces a significantly increased pulse frequency of gonadotropin-releasing hormone. Gonadotropin-releasing hormone stimulates follicle-stimulating hormone and luteinising hormone release with resulting oocyte maturation and an increase in oestra-diol levels.

■  Clomiphene citrate is given for 5 days beginning on day 2 after the start of menstruation or after a progesterone (10mg Provera, 5mg norethisterone)-induced withdrawal bleed if there is amenorrhoea.

■  The dosage is 25-50mg or 100 mg for 5 days. Clomiphene citrate should be commenced at as low a dose as 25-50 mg, especially with polycystic ovary syndrome. If ovulation occurs this dose is maintained. Otherwise the dose may be increased to a maximum of 150 mg per day for 5 days. Cycles should be monitored with oestrogen levels to identify a response, and once levels are at 500pmol/l ultrasound scans conducted to assess follicular growth and to avoid multiple pregnancy (if there are three or more follicles 18-22 mm sexual intercourse should be avoided unless the risk of multiple pregnancy is accepted). A serum progesterone on day 21 >20 IU/1 is indicative of ovulation. The dose should only be increased if there is no response to 50 mg clomiphene after three cycles. Of those women who will respond to 50 mg, only two thirds will do so in the first cycle. Doses of >150mg confer no benefit and only worsen the side effects, particularly of thickened cervical mucus.

■  Some women who have troublesome side effects with clomiphene may benefit from tamoxifen (20-40mg, days 2-6 of cycle). Side effects include visual disturbances (stop the drug immediately), multiple pregnancy (in approximately 10 per cent), abdominal tenderness, dizziness and nausea.

■  Clomiphene is currently licensed for only 6 months’ use in the UK because of the putative increased risk of ovarian cancer where an association was found between >12 months’ use and incidence of ovarian cancer. It may be due to the indication (unexplained infertility) rather than the medication. The Committee on Safety in Medicine recommended recently that clomiphene should not be used for more than six cycles because of this link. The tendency is to use it for longer than that because often the dosage needs to be adjusted. Patients should be fully informed of the risk.

Results

Up to 85 per cent of conceptions occur during the first three ovula-tory cycles. Nearly 50 per cent of women require increased dosages or longer treatment than 3 months. There is a positive correlation between the patient’s weight and the dose of clomiphene needed to induce ovulation.

■  Treatment induces ovulation in 70-80 per cent of women.

■  The conception rate is 40-50 per cent.

■  The multiple pregnancy rate is 8 per cent – 6.9 per cent twins, 0.5 per cent triplets, 0.3 per cent quadruplets, 0.13 per cent quintuplets.

■  Clomiphene may have an anti-oestrogenic action causing thickening of the cervical mucus which may impede the passage of sperm through the cervix.

■  When clomiphene is stopped oestrogen secretion continues, which produces a negative feedback control on the hypothalamus or release of gonadotropin-releasing hormone. The exponential rise in the oestradiol produced by the dominant follicle has a positive feedback effect on the hypothalamus. gonadotropin-releasing hormone release stimulates a surge of gonadotrophin output and ovulation occurs. Ovulation usually occurs 7 days after the last clomiphene tablet is ingested.

■  Ovulation is indicated by a serum progesterone on day 21, i.e. 2 weeks after the ingestion of the last clomiphene tablet.

■  The incidence of miscarriage is not increased with conceptions occurring after clomiphene treatment (15 per cent).

■  The incidence of congenital anomalies is approximately 2.5 per cent, which is no higher than those that occur after spontaneous conception.

■  Ovarian cysts occur in 5 per cent. Most will regress spontaneously within 4 weeks.

Side effects of clomiphene

■  Side effects are uncommon and infrequently interfere with treatment. They are dose related and are more frequent and more severe when higher doses of clomiphene are given.

■  The more common side effects are hot flushes (vasomotor symptoms similar to the menopause which disappear on discontinuation of the therapy, 10 per cent), abdominal discomfort due to distension, bloating, pain or soreness (5 per cent).

■  Ovarian enlargement and visual blurring is also reported.

■  Visual disturbances (1.5 per cent), described usually as blurring or spots or flashes (scintillating scotomata), increase in incidence with total dose and disappear within a few days or weeks after discontinuation.

■  Other less frequently reported symptoms include nausea, vomiting, increased nervous tension, depression, fatigue, dizziness or lightheadedness, insomnia, headache, breast soreness, heavier menses, weight gain, urticaria (0.6 per cent), urinary frequency, and moderate reversible hair loss (0.3 per cent).

■  In unresponsive women the dose of clomiphene may be increased to 10 days.

Tamoxifen is a similar drug to clomiphene. A triphenylethylene derivative, it appears to be as effective as clomiphene in inducing ovulation in anovulatory or oligo-ovulatory women. It may have less of an anti-oestrogenic effect on cervical mucus.

In the patient with polycystic ovary syndrome, if clomiphene therapy fails there is the option of either laparoscopic ovarian diathermy or gonadotrophin therapy.

Laparoscopic ovarian diathermy has the advantage of a 50 per cent success rate in terms of pregnancy while avoiding the risk of multiple pregnancy associated with the use of gonadotrophins, and therefore is particularly useful in patients with polycystic ovary syndrome. Ovarian diathermy or the use of gonadotrophins is indicated after a failure of conception with 9-12 treatment cycles of clomiphene.

Gonadotrophin therapy

Gonadotrophin therapy is indicated for women who have been treated with anti-oestrogens who have failed to ovulate or who have negative postcoital tests due to the anti-oestrogenic effect on cervical mucus.

It is also used for ovulation induction in those women who are anovulatory and failed to ovulate with clomiphene citrate or bromocriptine.

Gonadotrophins were initially urinary-derived human menopausal gonadotropins (hMGs or follicle-stimulating hormone). Modern follicle-stimulating hormone is made from recombinant technology. Gonadotrophins are glycoprotein hormones. Their activity can only be measured by bio-assay and not immunoassay. The cumulative live birth rate with gonadotrophin stimulation is 60 per cent, with multiple pregnancy rates of up to 20 per cent and miscarriage rates of up to 30 per cent, after 12 months. Down-regulation with gonadotropin-releasing hormone agonists and subsequent gonadotrophin stimulation may result in a two-fold increase in the pregnancy rate.

Principles of treatment

The amount of medication and duration of therapy vary in different patients, but also in different treatment cycles in the same patient. A certain basic follicle-stimulating hormone threshold is necessary to initiate follicular development, and this varies from cycle to cycle. The patient is monitored to determine when one or more mature pre-ovulatory follicles have developed. Maximal diameter of the dominant follicle is correlated with serum oestradiol levels. The total volume of all developing follicles also correlates with oestradiol concentration. One mature pre-ovulatory follicle can be identified in association with a serum oestradiol level of approximately 500pmol/l. If ultrasound imaging of the follicles is not done, serum oestradiol concentrations of 1000pmol/l may be presumed to indicate that at least one or two follicles have reached pre-ovulatory status. Human chorionic gonadotrophin is given when there is a mature pre-ovulatory follicle shown on ultrasound scanning (>18mm).

Protocol  for gonadotrophin administration

Hyperstimulation and multiple pregnancy ought to be avoided Traditionally 75-150IU of gonadotrophin was used and increased by 75 IU every 3-5 days. Low dose step-up regimens should now be used. Start with 37.5-50IU follicle-stimulating hormone, which is increased after 14 days if there is no response, and then by 37.5-50IU follicle-stimulating hormone every 7 days. Treatment cycles may be up to 28-35 days but the risk of multiple follicular growth is reduced. A 10^30 per cent increment in the dose of exogenous follicle-stimulating hormone is required for follicular growth. Ovulation is triggered with a single intramuscular injection of human chorionic gonadotrophin (10000IU). It is given when there is at least one follicle >18mm in diameter. It should not be given if there are three or more follicles larger than 16 mm in diameter or four follicles larger than 14 mm, as the risk of triplets is unacceptable.

After 3-5 days measure the serum oestradiol level. If the baseline concentration has doubled the same dose of gonadotrophin is given. If the oestradiol level is unchanged, the dose of gonadotrophin is increased by 50 per cent and the oestradiol level measured 3 days later. If the oestradiol level remains similar to the baseline level, the dose is increased by 50 per cent and the oestradiol level measured every 3 days until a response occurs. Whenever the oestradiol level has doubled, the new dose is maintained.

There is no value in increasing the initial dose before the fifth day because recruitment of follicles takes between 5 and 15 days. Further increases are made at 4-7 days. In subsequent cycles the starting dose is determined by the patient’s previous response.

In subsequent treatment cycles, therapy begins at that level. An ultrasound scan is done when the oestradiol level reaches about 500pmol/l. Scanning is repeated every 2-3 days until the mean diameter of the dominant follicle is 14 mm. After that scanning is done daily. When a follicle is >18mm the gonadotrophin is discontinued and 10000IU human chorionic gonadotrophin is given 24 hours later to cause ovum release. It should be withheld if there are three or more follicles 18 mm or more in diameter. This regimen should give ovulation rates approaching 100 per cent with 70 per cent conception rates. The pregnancy rate per cycle is approximately 18 per cent and the mean number of treatment cycles is three. Eight per cent of pregnancies are multiple. Ovarian enlargement may occur in up to 10 per cent of treatment cycles. Treatment should not be given for more than a year.

Gonadotropin-releasing hormone agonists

The use of gonadotropin-releasing hormone agonists in addition to gonadotrophin therapy enables accurate timing of ovulation and hence either intercourse or intrauterine insemination.

Use of gonadotropin-releasing hormone agonists

Luteinising hormone and follicle-stimulating hormone secretion is determined by the pulsatile secretion of luteinising hormone-releasing hormone/gonadotropin-releasing hormone, The half-life of gonadotropin-releasing hormone is 2-8 minutes. Intermittent pulsed administration of gonadotropin-releasing hormone results in sustained release of follicle-stimulating hormone and luteinising hormone, whereas continuous administration inhibits the secretion of both follicle-stimulating hormone and luteinising hormone. Repeated pulses of gonadotropin-releasing hormone stimulate an increase in the number of gonadotropin-releasing hormone receptors, or modulate a post-receptor response leading to self-priming or up-regulation. In contrast, constant infusions of gonadotropin-releasing hormone down-regulate by depleting receptors and therefore desensitising the post-receptor response.

Table Types of gonadotropin-releasing hormone analogues and recommended dose.

Generic name Trade name Half-life Administration route Recommended dose
Nonapeptides
Buserelin Suprefact, Suprecur 80min s.c., i.n. 200-500 µh/day 300-400µh three to four times daily
Goserelin Zoladex 4.5 hours s.c. implant 3.6mg/month
Nafarelin Synarel 4 hours i.n. 200-400µh twice daily

Gonadotropin-releasing hormone agonists act as if a constant gonadotropin-releasing hormone infusion was being given because of their high receptor affinity. After an initial flare effect there is down-regulation with a profound reduction in gonadotrophin secretion. By blocking the endogenous gonadotrophin secretion, especially the luteinising hormone surge, agonists improve the predictability of the ovarian response in women with polycystic ovary syndrome and in superovulation regimens for In vitro fertilisation.

Gonadotropin-releasing hormone agonists are given intranasally, subcutaneously or as a depo injection, either subcutaneously or intramuscularly.

Gonadotropin-releasing hormone agonists prevent the surge of pituitary gonadotrophin that occurs in response to the rising serum oestradiol levels produced by multiple ovarian follicles, thereby reducing the chance of spontaneous ovulation and where the cycle can be cancelled. They allow continuation of stimulation in cases of asynchronous follicular growth. The other advantage of gonadotropin-releasing hormone agonists is to provide ovarian stimulation protocols that can be timed to a convenient time for oocyte collection and embryo transfer, thus coordinating the patient, laboratory staff and clinician.

Down-regulation of the pituitary gland

Pretreatment with a gonadotropin-releasing hormone agonist alters the hormonal milieu and the ovarian response to gonadotrophin and the pregnancy rate among women with polycystic ovaries. The advantage of an agonist is that the frequency of spontaneous premature luteinising hormone surges in women with polycystic ovary syndrome is lower. However, the dose of gonadotrophin needed to achieve adequate follicular development is increased by 30-50 per cent with a gonadotropin-releasing hormone agonist. The gonadotropin-releasing hormone agonist must be terminated with giving the human chorionic gonadotrophin.

Gonadotropin-releasing hormone protocols

1   Long protocol

■  Commence the gonadotropin-releasing hormone agonist either in the mid-luteal phase of the preceding cycle or in the early follicular phase of the treatment cycle.

■  gonadotropin-releasing hormone agonists are continued after pituitary suppression and continued until the day of human chorionic gonadotrophin administration.

2  Short protocol

gonadotropin-releasing hormone agonists and gonadotrophin are started in the early follicular phase of the treatment cycle and continued until the day of human chorionic gonadotrophin administration.

3   Ultra-short protocol

The gonadotropin-releasing hormone agonist is only administered for 3 days at the beginning of the treatment cycle.

Laparoscopic ovarian drilling to induce normal cyclicity

■  The procedure involves four to ten ovarian punctures per ovary (8 mm depth at 40 W for 4 seconds) using insulated needle cautery.

■  It is inserted perpendicularly to the ovarian surface.

■  The hilum of the ovary and the ovarian blood supply should be avoided.

■  The ovarian surface is lavaged: 50-100 ml of crystalloid solution may be left in the peritoneal cavity to minimise ovarian adhesion formation.

Endocrine changes after laparoscopic ovarian drilling

■  Decrease in serum luteinising hormone concentrations

■  Decrease in serum androgen concentration due to destruction of androgen-producing ovarian stroma and drainage of follicles which have high androgen levels

■  These endocrine changes may persist up to 72 months after surgery.

Results

■  Ovulation rates up to 80 per cent.

■  Cumulative pregnancy rates up to 55 per cent

■  Normalisation of serum luteinising hormone levels

■  Low miscarriage rate – 14 per cent.

Pregnancy rates are higher after In vitro fertilisation in those previously treated with ovarian drilling. Women treated with ovarian drilling have a lower rate of hyperstimulation and cancellation of In vitro fertilisation cycles compared to those not treated.

Complications

■  Periadnexal adhesion formation

■  Premature ovarian failure

■  Minimising injury to the ovarian surface minimises adhesion formation

■  Washing out the peritoneal cavity decreases adhesion formation because it removes fibrin exudate from raw peritoneal surfaces. It is the fibrin surface that provides the matrix for fibroblast and capillary formation.

Hypogonadotrophic hypogonadism

■  This may be at the level of the pituitary or the hypothalamus.

■  Oestradiol levels are <100pmol/l.

■  Gonadotrophin levels are subnormal (5IU/1).

■  Ovulation can be optimally induced in women with intact pituitary function by application of pulsatile luteinising hormone-releasing hormone or gonadotropin-releasing hormone, administered s.c. or i.v. by infusion pump.

■  The injections are given at 90 minutes at a dose of either 15 µh s.c. or 5-10 |!g i.v.

■  This method of ovulation induction is physiological and runs very little risk of multiple pregnancy or ovarian hyperstimulation syndrome.

Complications of ovarian stimulation with gonadotrophins – ovarian hyperstimulation syndrome

Hyperstimulation can occur in the polycystic ovary because of the role of vascular endothelial growth factor. Ovarian hyperstimulation syndrome is a sudden increase in vascular permeability resulting in a massive extravascular exudate (manifesting ascites), and a corresponding profound depletion of intravascular volume, as shown by haemoconcentration and decreased urine output. Loss of protein into the third space causes a fall in plasma oncotic pressure which results in further loss of intravascular fluid.

Table Ovarian hyperstimulation syndrome -symptoms and signs.

Marked ovarian enlargement (>10cm)
Ascites
Pleural effusions
Haemoconcentration
Hypercoagu lability
Oliguria

Table Management of ovarian hyperstimulation.

Grade 1 Advise the patient to weigh herself daily and take abundant fluid. Weight gain more than 5kg or abdominal distension, nausea and vomiting should lead to hospitalisation
Grade II Intravenous therapy, progesterone, TED stockings, analgesia, paracetamol and pethidine for severe pain. Avoid non-steroidal anti-inflammatory drugs
Grade III Ascites, respiratory difficulty, decreased circulation and renal function. Admit to intensive care. Central venous pressure (CVP), renal function, input and output
Check haemoconcentration by measuring haematocrit, intravascular volume depletion and blood viscosity
Haematocrit greater than 45% is a serious sign, greater than 55% is life-threatening. Leucocytosis may be greater than 40000 x 109.
Measure body weight, serum urea, creatinine, electrolytes, serum albumin, liver function tests, coagulation profile: infusion of colloid maintains intravascular volume. Human albumin 50-100ml repeated as required, normal saline for rehydration. Consider abdominal paracentesis

Grade I (mild ovarian stimulation) – fluid accumulation, weight gain, abdominal distension and discomfort. Ultrasound shows enlarged ovaries with a diameter greater than 5 cm.

Grade II (moderate) – nausea and vomiting. Great abdominal distension and more discomfort and dyspnoea. Ascites is present.

Grade III (severe) – life-threatening condition where there is clinical evidence of contraction of the intravascular volume (subnormal central venous pressure with reduced cardiac output), severe expansion of the third space (tense ascites, pleural and pericardial effusions), severe haemoconcentration and hepatorenal failure. Intravascular thrombosis may occur, particularly cerebral.

Prevalence

Overall risk 4 per cent, severe form 0.25 per cent. With in vitro fertilisation 1-10 per cent, severe cases 0.25-2 per cent.

Risk factors

■  Polycystic ovaries

■  Younger women with greater ovarian responsiveness

■  Use of gonadotrophins

■  Development of multiple immature follicles during treatment

■  The use of human chorionic gonadotrophin when the ovaries have been overstimulated

■  An oestradiol level greater than 8000-10 000 pmol/1

■  Twenty or more oocytes.

Ovarian hyperstimulation syndrome can be avoided in the woman responding too much by stopping the treatment and avoiding giving the ovulatory dose of human chorionic gonadotrophin. Oocytes may be collected and fertilised in vitro and the embryos inserted on a later cycle to avoid the risk of ovarian hyperstimulation syndrome associated with any pregnancy that might get established.

Monitor the following

■  Degree of ascites

■  Oliguria

■  Rise in serum creatinine

■  Falling creatinine clearance

■  Haemoconcentration unresponsive to medical therapy

■  Severe oliguria or renal failure persisting – give dialysis. Careful cardiac assessment to avoid cardiac tamponade from pericardial effusion. Avoid hydrothorax – paracentesis for relief of dyspnoea.

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