An obese, 25-year-old woman with PCOS presents with infertility, which is secondary to anovulation…

An obese, 25-year-old woman with PCOS presents with infertility, which is secondary to anovulation.

(a) Critically appraise the non-medical methods by which
ovulation can be induced in this patient. (6 marks)

(b) Discuss the anti-oestrogens that could be used for ovulation induction. (7 marks)

Common mistakes
● Induction of ovulation and treatment for infertility in general
● Discussing options for infertility treatment
● Concentrating on drug therapy only
● Treatment of male infertility
● Details of IVF-ET
● Discussing treatment for non-fertility symptoms of PCOS
● Failure to critically appraise your answer

A good answer will include some or all of these points

(a) Critically appraise the non-medical methods by which ovulation can be induced in this
patient. (6 marks)

● Weight loss:
● Does not require medication
● Free of side-effects
● Requires no medication
● If successful, there is no increased risk of multiple pregnancy, and pregnancy complications related to obesity are reduced
● If weight loss is successful in inducing ovulation, it will, however, complement other
methods of induction ovulation
● For most patients, this is unlikely to work, mainly because of failure to lose weight
● Ovarian drilling:
● Either by laparoscopy or laparotomy – most commonly by laparoscopy
● Using laser or diathermy
● Associated with a high success rate and minimal risk of multiple pregnancy and
OHSS
● Risk of anaesthesia and difficulties in performing laparoscopy in obese patient
● Effectiveness is time limited

(b) Discuss the anti-oestrogens that could be used for ovulation induction. (7 marks)

● Clomifene citrate. Induces ovulation in 60–80 per cent of cases, but successful pregnancy in only 40–60 per cent of cases

● Risk of multiple pregnancy (approx. 10 per cent)
● OHSS
● Requires ultrasound scan (USS) to monitor follicular development (ideal)
● Increased risk of ovarian cancer
● Not recommended to be given more than 6 months after ovulation is achieved
● Can be given in escalating doses up to 150 mg on day 2–6 of cycle
● May be combined with other methods, e.g. weight loss and other medications (metformin)
● Other anti-oestrogens include cyclofenil, tamoxifen, and the aromatase inhibitors anastrozole and letrozole

● Expensive and have to be administered parentally
● Require serial monitoring by USS and serum oestradiol to help reduce the risk of OHSS
and time the administration of human chorionic gonadotropin (hCG)
● Given as combined follicle-stimulating hormone (FSH) and luteinising hormone
(Metrodin®) or as recombinant FSH. Recombinant FSH is free of protein, hence minimal risk of allergic reaction
● Gonadotropins can be given in three approaches starting on day 2–3 of the cycle:
● Regular dose step-up
● Chronic low dose step-up
● Step-down protocols
● Increased risk of multiple pregnancies and OHSS
● Concomitant use with gonadotropin-releasing hormone (GnRH) agonist not shown to
be of any real additional benefit but can be used in women who show premature luteinisation

Sample answer
(a) Critically appraise the non-medical methods by which ovulation can be induced in this
patient. (6 marks)

The first non-medical option is weight loss. It does not require medication, is free of sideeffects and is inexpensive. In addition, with successful induction of ovulation, pregnancy rates
are higher compared to that of other methods.

Weight loss does not increase the risk of multiple pregnancies and overweight-related complications of pregnancy are reduced.
Additionally, weight loss increases the success rate of other methods of induction ovulation.
The main drawback is the need for motivation and the fact that it may take some time to be
successful.
The other non-medical method is laparoscopic (although this can be done by laparotomy)
laser or diathermy drilling of the ovaries. However, the procedure-related risks are greater in
this obese woman. It is expensive and involves hospital care, even if this is only during the time of surgery. The complications of the procedure include visceral injury, gas embolism, infections, adhesion formation and those of GA.

In skilled hands, this may be best performed at the
time of laparoscopic assessment of tubal function. This option is not associated with an
increased risk of multiple pregnancies. Wedge resection of the ovary has generally been superseded by modern techniques, but may still be considered in some developing countries.

(b) Discuss the anti-oestrogens that could be used for ovulation induction. (7 marks)

Clomifene citrate is the most commonly used anti-oestrogen, usually administered in the early
menstrual phase. It is inexpensive and induces ovulation successfully in about 30–40 per cent
of patients with PCOS, although that rate may be as high as 80 per cent in properly selected
patients. The 6 months’ cumulative conception rate, where ovulation has been successfully
induced, is similar to that of normal fertility (60 per cent) with most occurring in the first six
ovulatory cycles.

It has the added advantage that the multiple pregnancy rate is only 5–10 per
cent and significant OHSS is rare compared to after ovulation induction with gonadotropins.
Unfortunately, because of the anti-oestrogenic effects, clomifene citrate may induce ovulation
but not result in successful pregnancy. Therefore, patients may often have to take multiple
courses before pregnancy can be achieved.

Clomifene is licensed for 6 months in the UK and
if being used beyond this duration, appropriate counselling must be offered.
Where clomifene citrate has been unsuccessful, cyclofenil could be the next option. It has
less anti-oestrogenic effects on the cervical mucus. It may theoretically be associated with
higher pregnancy rates than clomifene citrate. However, cyclofenil is more expensive and
associated with more side-effects when compared to clomifene citrate.
Other anti-oestrogens, such as the aromatase inhibitors anastrozole and letrozole, have
been used in a similar way to clomifene citrate and have been shown to improve ovulation
induction rates in those who are refractory to clomifene. Although the selective oestrogen
receptor modulator tamoxifen has been used only occasionally, it is another option.

Ovulation can be induced with human menopausal gonadotropin (hMG) or pure FSH
(Pergonal®, Normagon® or Metrodin®), extracted from the urine of postmenopausal women
or recombinant FSH. Recombinant FSH is free of extraneous proteins to which some patients
may develop allergic reactions or antibodies.

Gonadotropins are effective but more expensive
methods of ovulation induction that have to be administered parenterally (usually daily and
starting in the menstrual phase).

The patient should have follicular tracking and serial oestradiol monitoring to time the administration of hCG, in order to minimise the risk of multiple
pregnancies and OHSS.
Although there are several approaches to the use of gonadotropins, three are most common.
These are the regular dose step-up, chronic low dose step-up and the step-down protocols.

If
she is to have the regular dose step-up option, she will be started on FSH 150 IU/day on day
2–3 of her cycle and increased by 75 IU/day every 3–4 days according to ovarian response
assessed by serum oestradiol or ultrasound follicular measurement. Once 1–2 dominant

follicles reach 18 mm, hCG is administered. It is associated with a higher incidence of multiple
pregnancies and OHSS.
The next protocol that she could be offered is the chronic low dose step-up protocol. This is
aimed at reaching the FSH threshold gradually and thereby avoiding excessive stimulation and
development of multiple follicles.

The starting dose is about 37.5–75 IU/day of FSH and continued for 10–14 days followed by increases of 37.5 IU/day every week to a maximum of
225 IU/day. When the dominant follicle reaches 18 mm, hCG is administered.

The main disadvantage is that it may take longer to reach the FSH threshold and she will have to be counselled appropriately. This regimen is associated with fewer multiple pregnancies and a lower
risk of OHSS compared to the regular dose step-up protocol.

The last option is the step-down protocol whose aim is to mimic the physiological changes
of a normal menstrual cycle. She would be given FSH starting with 150 IU/day on day 2–3 of
cycle and follicular tracking monitored every 2–3 days.

Once the dominant follicle is at least
10 mm, the dose is reduced to 112.5/day followed by a further decrease to 75 IU/day after 3
days. This is continued until hCG administration, the timing of which is determined by the
size of the dominant follicle.
Combining gonadotropins with GnRH agonist has not been shown to confer any additional
benefits in women with PCOS and is therefore only appropriate in women with premature
luteinisation