Gonadotrophins for ovulation induction
The gonadotrophins (FSH and LH) are released from the pituitary and they stimulate the ovaries (Figure 10.1). Gonadotrophins have become commercially available using extraction techniques on urine from menopausal women (HMG) who have high levels of gonadotrophins. The objective of gonadotrophin therapy is to produce mature follicles, which can be released by injection of HCG.
For low-tech treatment the objective is to stimulate maturation preferably of one follicle but with a maximum of three follicles. Patients who fail to ovulate or conceive with clomiphene or tamoxifen are candidates for gonadotrophin therapy. Tubal patency, normal prolactin levels and satisfactory semen analysis are essential pre-re quisites. Patients with hypergonadotrophic hypogonadism (menopausal gonadotrophin levels) do not respond to gonadotrophin therapy. There have been a variety of regimens for the administration of gonadotrophins. The fixed regimen involves a predetermined dose administered in a single intra-muscular injection on three alternate days e.g. Days 1, 3 and 5 of the menstrual cycle and HCG is given three days later if the oestrogen response is in the accepted range.
In the variable regimen, gonadotrophins tended to be administered daily, the dose being adjusted according to plasma or urinary oestradiol results. In the early days of gonadotrophin therapy, the only investigation for monitoring ovarian response was oestrogen assay of urine or blood. Ultrasound tracking of follicular development (pelvic ultrasound), initially transabdominally and more recently by the transvaginal route, has provided a valuable addition for the monitoring of gonadotrophin therapy.
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- The influence of body weight on response to ovulation induction with gonadotrophins in 335 women with World Health Organization group II anovulatory infertility. (2006-01)
- No difference in cycle pregnancy rate and in cumulative live-birth rate between women with surgically treated minimal to mild endometriosis and women with unexplained infertility after controlled ovarian hyperstimulation and intrauterine insemination. (2006-02)
- Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: a meta-analysis. (2003-01)
- Clinical experience with recombinant follicle-stimulating hormone (FSH) and urinary FSH: A retrospective case- controlled analysis?
- (2001-01)
- Gonadotrophin induction of ovulation using a step-down dose regimen: single-centre clinical experience in 82 patients. (1995-01)
Risks with gonadotrophins
The risks of gonadotrophin therapy are:
- multiple pregnancy (twins, triplets etc.): rates are higher with gonadotrophins than clomiphene.
- ovarian hyperstimulation syndrome (OHSS) is more commonly associated with polycystic ovary syndrome and accordingly for these women, the quantity of gonadotrophin administered should be reduced. Some units continue to monitor oestrogen levels in addition to ultrasound but it has been shown that ultrasound alone can be used safely and efficiently.
As with clomiphene (8), there is concern that gonadotrophin therapy may be associated with an increased risk of ovarian cancer although the latest data does not support the earlier anxieties.
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- Treatment for infertility and risk of invasive epithelial ovarian cancer (1997)
- The feasibility of assessing women's perceptions of the risks and benefits of fertility drug therapy in relation to ovarian cancer risk (1997)
- Low multiple pregnancy rate in combined clomiphene citrate - Human menopausal gonadotropin treatment for ovulation induction or enhancement (1989)
Recombinant FSH in ovulation Induction
The most recent advance in gonadotrophin production involves recombinant DNA technology. The DNA code (Q32.1) for FSH has been defined and can be inserted into mammalian cells, which then produce the FSH. The resultant recombinant human FSH has become commercially available (Gonal-F - Serono; Puregon - Organon).
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Ovulation Induction - Summary
With the exception of primary ovarian failure (the menopause), ovulatory disorders can usually be successfully treated. Ovulation induction regimens depend on the underlying cause (infertility cause).
Sometimes appropriate advice may be all that is required. When weight loss is responsible for secondary amenorrhoea (amenorrhoea causes), improved diet leading to correction of your weight may prove to be successful.
The main drugs used to overcome anovulation are clomiphene (clomiphene)(clomiphene citrate), tamoxifen (tamoxifen infertility), bromocriptine (bromocriptene), metformin (12), and gonadotrophins (gonadotrophins).
risks of ovulation induction
There are three concerns associated with drugs used to induce ovulation:
- They are associated with a greater chance of multiple pregnancy. The general rate of twins in the population is one in every eighty deliveries but with clomiphene, it is one in twenty or a four-fold increase. Higher order multiple pregnancies (e.g. triplets and quads) can occur with clomiphene but this is rare. Injections of gonadotrophins are more likely than clomiphene to result in multiple pregnancy.
- Occasionally ovulation induction can lead to ovarian hypersensitivity syndrome (OHSS).
- Finally, there has been concern that ovulation induction treatments may increase the chance of ovarian cancer. A comparison was made of the risk of cancer among women who received clomiphene with the risk among infertile women who did not receive it. There were 11 invasive or borderline malignant ovarian tumors, as compared with an expected number of 4.41994-01. A confounding factor is that infertility is itself associated with an increased risk. Furthermore, the risk is reduced with secondary infertility and is dependent on the causation of the infertility.2004-01Several infertility units have reported their data. Some seemed to confirm the link between clomiphene and ovarian cancer but the majority have produced reassuring results.1999-02,2004-02 2006-01
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- Induction of ovulation and ovarian cancer: a critical review of the literature. (2006-01)
- Ovarian cancer risk associated with varying causes of infertility.(2004-01)
- Ovarian cancer risk after the use of ovulation-stimulating drugs.(2004-02)
- Fertility drugs and the risk of breast and ovarian cancers: Results of a long-term follow-up study. (1999)
- Ovulation induction and ovarian tumours: the debate continues.(1999-02)
- Ovulation induction, infertility, and ovarian cancer risk (1996)
- The risk of ovarian cancer after treatment for infertility (1995)
- Ovarian stimulation and ovarian tumours: a critical reappraisal (1995)
- Ovarian tumors in a cohort of infertile women (1994)
- Characteristics relating to ovarian cancer risk: Collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women (1992)
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- Ovulation induction using s.c. pulsatile gonadotrophin-releasing hormone: Effectiveness of different pulse fre quencies (1996)
- Investigation and treatment of amenorrhoea resulting in normal fertility (1979)
Ovulation Induction Monitoring
Monitoring may be required to confirm that ovulation is occurring and to ensure that too many follicles are not developing. Blood tests for progesterone levels around the twenty-first day of the cycle provide an indication of ovulation (Q9.17). Ultrasound monitoring of follicular development is helpful with tablet treatment (clomiphene and tamoxifen) and is really essential with gonadotrophins. When controlled ovarian hyperstimulation is undertaken in IVF protocols, oestradiol levels are used. The need for monitoring hormone levels in IVF protocols has been questioned.1998-01, 2006-01
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- Monitoring ovarian stimulation: are hormonal assessments necessary? (2006-01)
- Follicle tracking of women receiving clomiphene citrate for ovulation induction. (2005-01)
- The role of infertility nurses in ovulation induction programmes (2001)
- Comparison of several one-step home urinary luteinizing hormone detection test kits to OvuQuick. (2001-02)
- The usefulness of a urinary LH kit for ovulation prediction during menstrual cycles of normal women. (1996-01)
- Is it possible to run a successful ovulation induction program based solely on ultrasound monitoring? The importance of endometrial measurements (1991-01)
- The clinical value of Clearplan home ovulation detection kits in infertility practice. (1991-02)
- Single serum progesterone measurement in the mid-luteal phase as an index of ovulation.(1987-01)
- Plasma progesterone levels as an index of ovulation. (1983-01)
- The value of a single serum progesterone measurement in the midluteal phase as a criterion of a potentially fertile cycle ("ovulation") derived form treated and untreated conception cycles. (1982-01)
- Plasma oestradiol and progesterone estimation for the monitoring of induction of ovulation with clomiphene and chorionic gonadotrophin. (1975-01)
