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

308 REPRODUCTIVE ENDOCRINOLOGY
gynaecomastia and impotence are predictable dose-dependent
effects. There is an increased risk of thromboembolism.
Oestrogens are carcinogenic in some animals and there is an
increased incidence of endometrial carcinoma in women who
have uninterrupted treatment with exogenous oestrogen
unopposed by progestogens.
Pharmacokinetics
Oestrogens are absorbed by mouth and via the skin and mucous
membranes. The most potent natural oestrogen is oestradiol-17β
which is largely oxidized to oestrone and then hydrated to produce
oestriol. All three oestrogens are metabolized in the liver
and excreted as glucuronide and sulphate conjugates in the bile
and urine. Estimation of urinary oestrogen excretion provides a
measure of ovarian function. Ethinylestradiol has a prolonged
action because of slow hepatic metabolism with a half-life of
about 25 hours.
PROGESTOGENS
Progesterone is a steroid hormone involved in the female menstrual
cycle, pregnancy (it supports gestation) and embryogenesis.
Progesterone is the precursor of 17-hydroxyprogesterone
which is converted to androstenedione which subsequently is
converted to testosterone, oestrone and oestradiol. Progesterone
is produced in the adrenal glands, by the corpus luteum, the
brain and by the placenta.
Progestogens act on tissues primed by oestrogens whose
effects they modify. There are two main groups of progestogens,
namely the naturally occurring hormone progesterone
and its analogues, and the testosterone analogues, such as
norethisterone and norgestrel. All progestogens have antioestrogenic
and anti-gonadotrophic properties, and differ in
their potency and their side effects.
Uses of progesterone
The uses of progesterone are:
• to control anovulatory bleeding;
• to prepare the uterine lining in infertility therapy and
to support early pregnancy;
• for recurrent pregnancy loss due to inadequate
progesterone production;
• in the treatment of intersex disorders, to promote
breast development.
Uses of progestogens
The uses of progestogens are:
• as part of the combined oral contraceptive and in the
progestogen-only pill. Medroxyprogesterone acetate
administered by depot injection is used when parenteral
contraception is indicated.
• as an anti-androgen in androgen-sensitive tumours,
such as prostate cancer, e.g. cyproterone acetate;
• as part of hormone replacement therapy in women with
an intact uterus to counteract the effects of unopposed
oestrogen on the endometrium which can result in
endometrial carcinoma;
• endometriosis;
• in menstrual disorders, such as premenstrual tension,
dysmenorrhoea and menorrhagia;
• progestogens in common use include norethisterone,
levonorgestrel, desogestrel, norgestimate and gestodene,
which are all derivatives of norgestrel. These differ
considerably in potency. The newer progestogens,
desogestrel, gestodene and norgestimate produce good
cycle control and have a less marked adverse effect on
plasma lipids; however, studies have shown that oral
contraceptives containing desogestrel and gestodene are
associated with an increase of around two-fold in the risk
of venous thromboembolism compared to those
containing other progestogens and should be avoided in
women with risk factors for thromboembolic disease.
Desogestrel, drospirenone (a derivative of spironolactone
with anti-androgenic and anti-mineralocorticoid
properties) and gestodene should be considered for
women who have side effects, such as acne, headache,
depression, weight gain, breast symptoms and
breakthrough bleeding with other progestogens. The
progestogen norelgestromin is combined with
ethinylestradiol in a transdermal contraceptive patch.
Mechanism of action
Progestogens act on intracellular cytoplasmic receptors and
initiate new protein formation. Their main contraceptive effect
is via an action on cervical mucus which renders it impenetrable
to sperm. Nortestosterone derivatives are partially
metabolized oestrogenic metabolites which may account for
some additional anti-ovulatory effect. A pseudodecidual change
in the endometrium further discourages implantation of the
zygote.
Pharmacokinetics
Progesterone is subject to presystemic hepatic metabolism and
is most effective when injected intramuscularly or administered
sublingually. It is excreted in the urine as pregnanediol
and pregnanelone. It has prolonged absorption and an elimination
half-life of 25–50 hours. It is highly protein bound.
Norethisterone, a synthetic progestogen used in many oral contraceptives,
is rapidly absorbed orally, is subject to little presystemic
hepatic metabolism and has a half-life of 7.5–8 hours.
THE COMBINED ORAL CONTRACEPTIVE
Since the original pilot trials in Puerto Rico proved that steroid
oral contraception was feasible, this method has become the
leading method of contraception world-wide. Nearly 50% of
all women in their twenties in the UK use this form of contraception.
It is the most consistently effective contraceptive
method and allows sexual relations to proceed without interruption,
but it lacks the advantage of protection against sexually
transmitted disease that is afforded by condoms. The most
commonly used oestrogen is ethinylestradiol. The main contraceptive
action of the combined oral contraceptive (COC) is
to suppress ovulation by interfering with gonadotrophin