A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

312 REPRODUCTIVE ENDOCRINOLOGY
Oestrogens used in HRT include conjugated oestrogens,
mestranol, estradiol, estriol and oestropipate. Progester-ones
used in HRT include medroxyprogesterone, norgestrel,
norethisterone, levonorgestrel and dydrogesterone. Tibolone
has oestrogenic, progestogenic and weak androgenic activity.
Key points
HRT is much less used now because of worries about
increased cardiovascular events and hormone-sensitive
cancers (especially breast). Absolute contraindications:
• pregnancy;
• oestrogen-dependent cancers;
• active thrombo-embolic disease;
• liver disease;
• undiagnosed vaginal bleeding;
• breast-feeding.
REPRODUCTIVE HORMONE ANTAGONISTS
Uses
There are a number of agents now available that are used in
early and advanced breast cancer due to their antagonistic or
inhibitory effect on oestrogen, breast cancer commonly being
an oestrogen-sensitive tumour.
Oestrogen receptor antagonists include tamoxifen which
is licensed for breast cancer and anovulatory infertility, fulvestrant
which is licensed for the treatment of oestrogen
receptor-positive metastatic or locally advanced breast cancer
in post-menopausal women, and toremifene which is
licensed for hormone-dependent metastatic breast cancer in
post-menopausal women.
The aromatase inhibitors block the conversion of androgens
to oestrogens in the peripheral tissues. They do not inhibit
ovarian oestrogen synthesis and are not suitable for use in premenopausal
women who will continue to secrete ovarian
oestrogens. Currently licensed agents include anastrozole,
letrozole and exemestane.
The gonadorelin analogue goserelin is licensed for the
management of advanced breast cancer in premenopausal
women. It acts by initially stimulating and then depressing
luteinizing hormone released by the pituitary, which in turn
reduces oestrogen production.
Clomifene and tamoxifen are used in the treatment of
female infertility due to oligomenorrhoea or secondary amenorrhoea
(for example, that associated with polycystic ovarian
disease). Both drugs can induce gonadotrophin release by
occupying oestrogen receptors in the hypothalamus, thereby
interfering with feedback mechanisms. As an adjunct, chorionic
gonadotrophin is sometimes used.
Clomifene is used primarily for anovulatory infertility.
Patients should be warned about the risks of multiple births. It
is contraindicated in those with liver disease, ovarian cysts,
hormone-dependent tumours and abnormal uterine bleeding
of undetermined cause.
Side effects of clomifene include visual disturbances, ovarian
hyperstimulation, hot flushes, abdominal discomfort,
occasionally nausea, vomiting, depression, insomnia, breast
tenderness, headache, intermenstrual spotting, menorrhagia,
endometriosis, convulsions, weight gain, rashes, dizziness
and hair loss.
GONADOTROPHINS
Follicle-stimulating hormone (FSH) and luteinizing hormone
(LH) together, or follicle-stimulating hormone alone, and
chorionic gonadotrophin, are used in the treatment of infertility
in women with proven hypopituitarism or who have not
responded to clomifene, or in superovulation treatment for
assisted conception, for example in vitro fertilization (IVF).
DRUGS FOR SUPPRESSION OF LACTATION
Bromocriptine is a dopamine agonist and inhibits the release
of prolactin by the pituitary. It is used for the treatment of
galactorrhoea and cyclical benign breast disease, as well as the
treatment of prolactinomas.
Cabergoline has actions and uses similar to those of
bromocriptine, but its duration of action is longer. It has a different
side-effect profile from bromocriptine and patients
who may not tolerate the latter may be able to tolerate cabergoline
and vice versa.
Although bromocriptine and cabergoline are licensed to
suppress lactation, they are not recommended for routine suppression
or for the relief of symptoms of postpartum pain and
breast engorgement that can be adequately treated with simple
analgesics and support.
PROSTAGLANDINS AND OXYTOCIC DRUGS
Prostaglandins and oxytocics are used to induce abortion, or
induce or augment labour, and to minimize blood loss from
the placental site. The commonly used drugs include oxytocin,
ergometrine and the prostaglandins. All work by
inducing uterine contractions with varying degrees of pain
according to the strength of the contractions induced.
Synthetic prostaglandin E 2 (dinoprostone) is used for the
induction of late (second-trimester) therapeutic abortion,
because the uterus is sensitive to its actions at this stage,
whereas oxytocin only reliably causes uterine contraction later
in pregnancy.
Dinoprostone is preferred to oxytocin for the induction of
labour in women with intact membranes regardless of parity
or cervical favourability. Both are equally effective in inducing
labour in women with ruptured membranes. However, oxytocin
is preferred for this, because it lacks the many side
effects of prostaglandin E 2 that relate to its actions on extrauterine
tissues. These include nausea, vomiting, diarrhoea,
flushing, headache, hypotension and fever.
Dinoprostone is available as vaginal tablets, pessaries and
vaginal gels. Oxytocin is administered by slow intravenous