Fertility and subfertility 87

methylene blue insufflation and any co-morbidities

such as endometriosis or adhesions treated. If successful

then regular ovulations can continue for years. Patients

are warned of the risks of surgery, including periovarian

adhesion formation and, rarely, ovarian failure.

Gonadotrophins (see below).

Gonadotrophin induction of ovulation

These are used when clomifene has failed, but also in

hypothalamic hypogonadism if the weight is normal.

Recombinant or purified urinary FSH ± LH acts as a

substitute for the normal pituitary production and is

given by daily subcutaneous injection to stimulate fol-

licular growth. The result is often maturation of more

than one follicle. For PCOS patients a ‘low-dose step-up’

regimen is used in which the gonadotrophin dose is

increased in small increments every 5–7 days until the

ovaries begin to respond. This reduces the multiple

pregnancy rate to <10%. Follicular development is

monitored with ultrasound. Once a follicle is of a size

adequate for ovulation (about 17 mm), the process can

be artificially stimulated by injection of hCG (which is

structurally similar to LH) or recombinant LH. As an

alternative to gonadotrophin induction of ovulation,

women with hypothalamic hypogonadism can use a

continuous subcutaneous GnRH pump. This stimulates

FSH and LH production from the pituitary in a physi-

ological manner and achieves normal pregnancy and

multiple pregnancy rates. However, the need to wear the

pump continuously limits the method’s acceptability.

Treatment of PCOS

Clomifene is the traditional first-line ovulation induction

drug in PCOS. It is limited to 6 months’ use and results

in ovulation and live birth rates of around 70% and 40%,

respectively. Clomifene is an antioestrogen, blocking

oestrogen receptors in the hypothalamus and pituitary.

As gonadotrophin release is normally inhibited by oes-

trogen, it increases the release of FSH and LH. Effec-

tively, therefore, it ‘fools’ the pituitary into ‘believing’

there is no oestrogen. As it is only given at the start of

the cycle, from days 2 to 6, it can initiate the process of

follicular maturation which is thereafter self-perpetuating

for that cycle. Clomifene cycles should be monitored by

transvaginal ultrasound, at least in the first month, to

assess ovarian response (both under and over) and

endometrial thickness. If no follicles develop then the

dose in subsequent cycles is increased from 50 mg/day to

100 mg and, if necessary, a maximum of 150 mg/day. If

three or more follicles develop then cycle cancellation is

generally indicated to reduce the risk of multiple preg-

nancy (overall 10%). As clomifene is an antioestrogen it

has negative effects at the endometrium and, on higher

doses, may cause a thin endometrium of <7 mm. This

might explain the live birth rate (40%), which is lower

than expected in view of the good ovulation rates (70%).

If ovulation does not occur despite dose escalation

(‘clomifene resistance’) then second-line treatments

include:

Metformin is an oral insulin sensitizing drug which aims

to restore ovulation. It does not promote multiple ovu-

lation so there is no increase in multiple pregnancies

(and no need for scan monitoring). When used alone it

has a lower live birth rate compared to clomifene, so

clomifene continues to be the first-line treatment of

choice (NEJM 2007; 356: 551). Metformin increases the

effectiveness of clomifene in clomifene-resistant women.

It treats hirsutism so may be a suitable first-line fertility

treatment for anovula tory women who want hirsutism

treated and to avoid multiple pregnancy. Additional

benefits, when metformin is continued during preg-

nancy, may include a reduction in both early miscar-

riage and the development of gestational diabetes,

which are more common with PCOS.

Laparoscopic ovarian diathermy is as effective as gona-

dotrophins (Cochrane 2007: CD001122) and with a

lower multiple pregnancy rate. Each ovary is monopolar

diathermied at a few points for a few seconds. During

the same operation tubal patency can be tested using

Inducing ovulation

If polycystic ovary

syndrome (PCOS):

Weight loss and lifestyle changes.

If inappropriate/fails . . .

Clomifene. If fails . . .

Add metformin

Gonadotrophins

Ovarian diathermy. If no

success . . .

In vitro fertilization (IVF)

If hypothalamic

hypogonadism:

Restore weight

Gonadotrophins if weight normal

If hyperprolactinaemia: Bromocriptine or cabergoline

If ovulation or pregnancy does not occur following

second-line treatments then in vitro fertilization (IVF)

[→ p.92] is the next step.