Progesterone
Adverse Effects
Progesterone and the progestogens may cause gastrointestinal
disturbances, changes in appetite or
weight, fluid retention, oedema, acne, chloasma
(melasma), allergic skin rashes, urticaria, mental depression,
breast changes including discomfort or occasionally
gynaecomastia, changes in libido, hair loss,
hirsutism, fatigue, drowsiness or insomnia, fever,
headache, premenstrual syndrome-like symptoms, and
altered menstrual cycles or irregular menstrual bleeding.
Anaphylaxis or anaphylactoid reactions may occur
rarely. Alterations in the serum lipid profile may occur,
and rarely alterations in liver-function tests and jaundice.
Pain, diarrhoea, and flatulence have followed rectal
use. Injection-site reactions have followed parenteral
use.
Adverse effects vary depending on the dose and type of
progestogen. For example, androgenic effects such as
acne and hirsutism are more likely to occur with nortestosterone
derivatives such as norethisterone and
norgestrel. These derivatives may also be more likely
to adversely affect serum lipids. Conversely, adverse
effects on serum lipids appear less likely with
gestodene and desogestrel, but these 2 drugs have been
associated with a higher incidence of thromboembolism
than norethisterone and norgestrel when used in
combined oral contraceptives. High doses
of progestogens such as those used in treating cancer
have also been associated with thromboembolism. For
a discussion of the effect of progestogens on the cardiovascular
risk profile of menopausal HRT see p.2073.
Breakthrough uterine bleeding is more common with
oral progestogen-only contraceptives than when progestogens
are used for menstrual irregularities or as
part of menopausal HRT.
Some progestogens when given during pregnancy
have been reported to cause virilisation of a female fetus.
This appears to have been associated with those
progestogens with more pronounced androgenic activity
such as norethisterone; the natural progestogenic
hormone progesterone and its derivatives such as dydrogesterone
and medroxyprogesterone do not appear
to have been associated with such effects.
Carcinogenicity. In a cohort study1 of women aged 40 to 64
years, the premenopausal use of oral progestogens alone, mainly
for benign breast, uterine, and ovarian conditions, and irregular
menstruation, was not associated with an increased risk of breast
cancer. However, the data did suggest that there was an increased
risk for current users of progestogens for longer than 4.5 years
(relative risk 1.44, 95% confidence interval 1.03 to 2.00) compared
with women who had never used progestogens. Limitations
of this study included the lack of analysis of different progestogens
or a record of the reasons for progestogen treatment.
Effects on the skin. Auto-immune progesterone dermatitis includes
reactions such as eczema, urticaria, and angioedema that
usually begin 3 to 10 days before the onset of menstrual flow and
end 1 to 2 days into menses, which correlates with raised endogenous
progesterone concentrations during the luteal phase of the
menstrual cycle. The onset of the condition can be as early as
menarche, and many women have never been exposed to exogenous
progesterone, but it has also occurred in women with a
history of oral contraceptive use. Management has been based on
the suppression of endogenous progesterone secretion and oral
contraceptives are usually tried first, although they appear to
have limited success possibly because of the progestogen component.
Other drugs that have been used include corticosteroids,
conjugated oestrogens, gonadorelin analogues, androgens, and
tamoxifen, but all have significant adverse effects associated
with long-term use. Bilateral oophorectomy has been used in severe
cases, when drug therapy has been unsuccessful.
A woman with a history of auto-immune progesterone dermatitis
developed pruritic, pink, oedematous plaques and macules on
the upper thighs, axillae, and buttocks after the use of vaginal
progestogen gel during infertility treatment. The reaction was
managed with topical corticosteroids. In another woman, with a
history of chronic urticaria exacerbated by progesterone, the use
of progesterone and various other progestogens as a component
of HRT after oophorectomy caused urticaria and angioedema.
Desensitisation using micronised progesterone was successful in
this case.
Precautions
Progesterone and the progestogens should be used with
caution in patients with hypertension, cardiac or renal
impairment, asthma, epilepsy, and migraine, or other
conditions which may be aggravated by fluid retention.
Progestogens can decrease glucose tolerance and diabetic
patients should be carefully monitored. They
should also be used with care in persons with a history
of depression. High doses should be used with caution
in patients susceptible to thromboembolism.
Progesterone and the progestogens should not be given
to patients with undiagnosed vaginal bleeding, nor to
those with a history or current high risk of arterial disease
and should generally be avoided in hepatic impairment,
especially if severe. Unless progestogens are
being used as part of the management of breast or genital-
tract carcinoma they should not be given to patients
with these conditions.
Although progestogens have been given as hormonal
support during early pregnancy such use is not now
generally advised. However, the use of a progesteronetype
progestogen might still be considered for women
who are progesterone-deficient. Such use may prevent
spontaneous evacuation of a dead fetus, therefore careful
monitoring of pregnancy is required. Progestogens
should not be used diagnostically for pregnancy testing
and should not be given in missed or incomplete abortion.
Breast feeding. A large study compared a contraceptive progesterone-
releasing vaginal ring and a copper IUD for 1 year in
breast-feeding women. There was little difference in infant
weight gain during the study, although at 12 months the infants
of mothers using the IUD were breast-fed less frequently, receiving
more supplementary feeding, and were heavier. There was no
adverse effect of progesterone on lactation or infant growth. Further
smaller studies have also found no adverse effect on lactation
or infant growth. The American Academy of Pediatrics has
found no reports of adverse effects in breast-fed infants of mothers
given progesterone, and therefore considers it to be usually
compatible with breast feeding.
Porphyria. Progesterone and progestogens have been associated
with acute attacks of porphyria and are considered unsafe in
patients with porphyria (but medroxyprogesterone has been used
with buserelin to suppress premenstrual exacerbations of porphyria. Progestogens should generally be avoided
by all women with porphyria; however, where non-hormonal
contraception is inappropriate, progestogens may be used with
extreme caution if the potential benefit outweighs the risk. The
risk of an acute attack is greatest in women who have had a previous
attack or are under 30 years of age. Long-acting progestogen
preparations should never be used in those at risk.
Pregnancy. In Hungary, where 30% of all pregnant women
were given hormonal support therapy with progestogens during
the early 1980s, a case-control study suggested that there was a
causal relationship between such treatment and hypospadias in
their offspring. Mixed results have been reported in other studies
of the association between maternal progestogen use and the
risk of hypospadias, but the indications and types of progestogens
used in early pregnancy have also changed over time
(for example, withdrawal bleeding induced by progestogens as a
form of pregnancy testing is no longer used, and progestogen
luteal support in early pregnancy is no longer recommended for
routine use; see also Miscarriage, below). Nevertheless, results
from a more recent case-control study of deliveries between October
1997 and December 2000 suggested an increase in risk of
at least twofold.
There have also been reports of nongenital malformations, including
limb reduction defects, neural tube defects, and congenital
heart malformations, following intra-uterine exposure to progestogens
in early pregnancy. However, numerous analyses of
accumulated data have found no evidence of a recognisable malformation
syndrome.
Interactions
Enzyme-inducing drugs such as carbamazepine, griseofulvin,
phenobarbital, phenytoin, and rifampicin may
enhance the clearance of progesterone and the progestogens.
These interactions are likely to reduce the efficacy of progestogen-only contraceptives, and additional or alternative contraceptive
measures are recommended.
Aminoglutethimide markedly reduces the plasma concentrations
of medroxyprogesterone acetate and megestrol,
possibly through a hepatic enzyme-inducing effect;
an increase in progestogen dose is likely to be
required.
Since progesterone and other progestogens can influence
diabetic control an adjustment in antidiabetic dosage
could be required. Progestogens may inhibit
ciclosporin metabolism leading to increased plasmaciclosporin
concentrations and a risk of toxicity.
Pharmacokinetics
Progesterone has a short elimination half-life and undergoes
extensive first-pass hepatic metabolism when
given orally; oral bioavailability is very low although it
may be increased somewhat by an oily vehicle and by
micronisation. Progesterone is absorbed when given
buccally, rectally, or vaginally, and rapidly absorbed
from the site of an oily intramuscular injection.
Various derivatives have been produced to extend the
duration of action and to improve oral activity. Esters
of progesterone derivatives such as hydroxyprogesterone
caproate are used intramuscularly, and megestrol
acetate is orally active. The ester medroxyprogesterone
acetate is used orally and parenterally. 19-Nortestosterone
progestogens have good oral activity because the
17-ethinyl substituent slows hepatic metabolism.
Progesterone and the progestogens are highly protein
bound; progesterone is bound to albumin and corticosteroid
binding globulin; esters such as medroxyprogesterone
acetate are principally bound to albumin; and
19-nortestosterone analogues are bound to sex-steroid
binding globulin and albumin. Progesterone is metabolised
in the liver to various metabolites including
pregnanediol, which are excreted in the urine as sulfate
and glucuronide conjugates. Similarly, progestogens
undergo hepatic metabolism to various conjugates,
which are excreted in the urine. Progesterone is distributed
into breast milk.
Uses and Administration
Progesterone is a natural hormone whereas progestogens
are synthetic compounds, derived from progesterone
or 19-nortestosterone, with actions similar to
those of progesterone.
Progestogens derived from 19-nortestosterone are used
as hormonal contraceptives, either alone
or combined with an oestrogen. The progesterone derivative
medroxyprogesterone acetate is also used, and
progesterone itself has been used.
Progestogens, and sometimes progesterone, are used
with oestrogens for menopausal HRTto reduce
the increased risk of endometrial hyperplasia and
carcinoma that occurs when long-term oestrogen therapy
is unopposed.
Similarly, drugs with progestogenic actions may be
used in menstrual disorders as dysmenorrhoea and menorrhagia associated with dysfunctional
uterine bleeding. Progestogens may also be
used in the management of endometriosis. Although
progestogens and progesterone have been used
for the management of the premenstrual syndrome,
such a practice is of debatable value.
Progestogens may be valuable in advanced endometrial
cancer and have been tried in some other
malignancies. The progestogens typically used for malignant
disease include medroxyprogesterone acetate,
megestrol, and norethisterone. Some progestogens
such as megestrol and medroxyprogesterone are used
for the cachexia wasting associated with severe illness
including cancer and AIDS.
Progestogens have been widely advocated for either
the prevention of recurrent miscarriage the treatment
of threatened miscarriage. However,
there is little evidence of any benefit from such a practice
and the use of progestogens in early pregnancy is
not now generally advised, with the exception of the
use of progesterone or a progesterone derivative in
women who are progesterone deficient (see also Precautions,
above). Progesterone is, however, the preferred
drug for luteal support in women undergoing assisted
reproductive techniques such as IVF.
USES AND ADMINISTRATION OF PROGESTERONE. Progesterone
is usually given as an oily intramuscular injection,
a vaginal gel or pessaries, or as suppositories.
Preparations containing micronised progesterone are
also available for oral and vaginal use.
In dysfunctional uterine bleeding or amenorrhoea 5 to
10 mg daily of progesterone may be given by intramuscular
injection for about 5 to 10 days until 2 days
before the anticipated onset of menstruation. Alternatively,
progesterone may be given for amenorrhoea as
a vaginal gel at a usual dose of 45 mg on alternate days
for up to 6 doses; the dose may be increased to 90 mg
in those who do not respond to the lower dose. An oral
dose of 400 mg given daily at bedtime for 10 days may
also be used for amenorrhoea.
In women with a history of recurrent miscarriage and
proven progesterone deficiency, twice weekly intramuscular
injection (increased to daily if necessary) of
25 to 100 mg of progesterone, from about day 15 of the
pregnancy until 8 to 16 weeks, has been used. The dose
may be increased to 200 mg daily if necessary. Vaginal
doses of micronised progesterone 200 to 400 mg daily,
in 2 divided doses, have also been given until week 12
of pregnancy. A similar intramuscular schedule has
been used for luteal support in IVF or gamete intra-fallopian
transfer techniques with treatment beginning on
the day of transfer of embryo or gametes. Alternatively,
progesterone may be given vaginally in assisted reproduction,
but doses can vary widely depending on
the preparation. A vaginal gel may be given at a dose
of 90 mg daily; it is given for 30 days if pregnancy occurs,
and may be continued until there is placental autonomy
(up to 10 to 12 weeks). A dose of 90 mg twice
daily has been used in women with ovarian failure. A
vaginal tablet containing micronised progesterone
100 mg may be given 2 or 3 times daily; treatment is
started at oocyte retrieval and continued for up to 10
weeks. Some soft capsules containing micronised progesterone
may also be suitable for intravaginal use in a
dose of 400 to 600 mg daily, in 2 or 3 divided doses,
from the day of gonadotrophin administration until
week 12 of pregnancy.
Progesterone may be given vaginally or rectally in doses
of 200 mg daily to 400 mg twice daily for the management
of the premenstrual syndrome. Treatment
usually starts on day 12 to 14 of the menstrual cycle
and continues until the onset of menstruation. Similar
vaginal or rectal doses have also been used in the treatment
of puerperal (post-natal) depression.
Progesterone has been given as the progestogen component
of menopausal HRT. Soft capsules containing
micronised progesterone are available in some countries
for oral use, given in a dose of 200 mg daily at
bedtime for 12 to 14 days of each month. Alternatively,
a dose of 100 mg daily may be given from day 1 to 25
of each cycle, resulting in less withdrawal bleeding.
A progesterone-releasing intra-uterine device has been
used as a hormonal contraceptive; the device contains
38 mg of progesterone and is effective for up to 12
months. A vaginal ring device that releases 10 mg of
progesterone daily is used in some countries for contraception
in lactating women. The first ring is inserted 6
weeks after delivery, then replaced every 90 days.
Administration. A number of progesterone creams for topical
application to the skin are promoted in various countries for the
management of menopausal symptoms and conditions associated
with progesterone deficiency. These are sometimes described
as containing โnaturalโ progesterone or phytoprogesterone from
plant sources. However, many of these products are available
without prescription or medical consultation and there has been
some concern about their safety and efficacy. Reviews have
found early studies reporting that absorption of progesterone
from these creams was minimal. However, a later study3 using
liquid chromatography-tandem spectrometry of whole blood reported
that steady-state progesterone exposure was similar for
women given either oral micronised progesterone or topical
cream. The authors suggested that the differences between their
results and previous studies were likely to have been caused by
the use of different analytical techniques, and that women using
these creams may in fact be exposed to higher systemic concentrations
of progesterone than previously thought. Some proponents
of topical progesterone therapy have questioned the importance
of using serum concentrations as a marker for absorption.
A review4 concluded that available serum-progesterone concentrations
probably remain low after topical use and that further
studies on the pharmacokinetics of topical progesterone are
needed. In terms of efficacy, a number of small controlled studies
have not shown progesterone cream to be any better than placebo
for the management of menopausal vasomotor symptoms or the
prevention of bone loss, and mixed results have been reported
regarding the prevention of endometrial proliferation associated
with oestrogen therapy.
Menorrhagia. Menorrhagia, or excessive menstrual bleeding,
is usually defined as a blood loss exceeding 80 mL per menstrual
period, compared with a normal loss of about 30 mL. However,
many women consider losses below 80 mL to be excessive
particularly if โfloodingโ occurs. Although not life-threatening,
menorrhagia can lead to iron deficiency anaemia and considerably
impair quality of life. Menorrhagia may be associated with
pelvic disorders such as fibroids or endometriosis, the use of copper
IUDs, or some systemic disorders. However, most commonly
it is associated with dysfunctional uterine bleeding; a
term used to denote frequent, prolonged or heavy uterine bleeding
for which no specific cause is found (essential, idiopathic, or
primary menorrhagia). Both ovulatory (regular) and anovulatory
cycles may give rise to dysfunctional uterine bleeding. In general,
medical treatment is used initially in women with no underlying
uterine abnormalities. The most commonly used drugs are
NSAIDs, tranexamic acid, combined oral contraceptives, and
progestogens, and choice of therapy may be influenced by the
contraceptive needs of the patient. Surgery can be used if medical
management is ineffective, and may be considered for firstline
treatment in selected patients.
NSAIDs such as mefenamic acid, ibuprofen, and naproxen have
been widely used. They reduce menstrual blood loss by about 20
to 50%, and there does not seem to be evidence to suggest that
one NSAID is more effective than another. They are taken only
during the menstrual phase, which reduces adverse effects, and
probably improves patient compliance; they also have the benefit
of relieving dysmenorrhoea. Systematic review suggests
that NSAIDs are less effective than tranexamic acid, danazol,
and intra-uterine levonorgestrel in reducing bleeding. NSAIDs
are considered a suitable option when hormonal therapy is not
acceptable. They should be stopped if symptoms do not improve
within three menstrual cycles, but can be used for as long as the
patient finds them to be beneficial.
Given during menstruation tranexamic acid menstrual
blood loss by about half; the benefits of tranexamic therapy
have been confirmed by systematic review. Like NSAIDs, tranexamic
acid is considered a suitable option when hormonal therapy
is not acceptable. It should be stopped if symptoms do not
improve within three menstrual cycles, but can be used for as
long as the patient finds it to be beneficial. Etamsylate been
used for menorrhagia, but it is less effective than NSAIDs and
tranexamic acid, and is no longer recommended.
In women who require contraception, a combined oral contraceptive
appears to be effective, although good evidence of this
is actually lacking. It has been suggested that extended-cycle
regimens should be considered for women with menorrhagia, as
there are fewer bleeding episodes per year of treatment. Traditional
therapy with progestogens as norethisterone or medroxyprogesterone
given during the luteal phase appears to be
ineffective in women with normal ovulatory cycles, although
cyclical therapy may be of benefit in anovulatory patients as it
imposes a cycle. Progestogen therapy for 21 days of the cycle
results in a significant reduction in menstrual blood loss, but
is associated with adverse effects that may limit its acceptability.
Long-acting injectable progestogens, such as medroxyprogesterone
acetate, reduce menstrual blood loss or induce amenorrhoea
when they are used as contraceptives. They have therefore been
used for menorrhagia, although specific studies for this indication
are lacking.
More recently, a contraceptive levonorgestrel-containing IUD
has been shown to be very effective in reducing menstrual blood
loss in menorrhagia. UK guidelines suggest that it should be
considered first when either hormonal or non-hormonal treatment
is acceptable and long-term use is anticipated, although
comparative data are scanty. There is also some evidence that it
may be an effective alternative to surgery, but data from longterm
follow-up are needed. As there can be changes in bleeding
pattern associated with this device, particularly in the first few
cycles, use for at least 6 months is advised to enable full assessment
of benefit.
Danazol is also effective, producing about a 50% reduction in
menstrual blood loss,1 but has significant adverse effects and
treatment is usually limited to 3 to 6 months. Gonadorelin analogues
are effective for menorrhagia associated with fibroids. When used pre-operatively for endometrial thinning,
they produce more consistent results than danazol. Gonadorelin
analogues may therefore be considered before surgery or
when other options for fibroids are contra-indicated, but โaddbackโ
hormone replacement is recommended for the management
of adverse effects from oestrogen deficiency or if they are
used for more than 6 months.
In patients who fail to respond to drug treatment, or in whom
such therapy is inappropriate, various surgical options exist.
Conservative surgical techniques, where the endometrium is ablated
or resected, are increasingly being used, and are an effective
alternative to hysterectomy. Hysterectomy is the ultimate
therapy, but is associated with significant morbidity.
Miscarriage. Threatened miscarriage is a common complication
of pregnancy that presents before 20 weeks of gestation as
vaginal bleeding, with or without abdominal pain, while the cervix
is closed and the fetus is viable. Endogenous progesterone is
normally produced by the corpus luteum to maintain pregnancy,
and low concentrations have been associated with pregnancy
loss. Progestogen therapy has therefore been widely used in the
treatment of threatened miscarriage, but there is a paucity of
clinical study data to support routine use. Similarly, progestogens
have been used prophylactically to prevent miscarriage,
but studies have suffered from various limitations. A systematic
review4 found no evidence to support routine use, but
there was limited evidence to suggest that women with a history
of recurrent miscarriage (3 or more consecutive miscarriages)
might gain some benefit. The BNF that progestogen
prophylaxis in women with a history of recurrent miscarriage is
not recommended.
Premature labour. Recommendations have been made regarding
progesterone therapy for the prevention of premature
birth in women at risk of preterm delivery.
Premenstrual syndrome. Progestogen therapy was once
popular for premenstrual syndrome, but beneficial responses
have not been universally achieved and the theory that progesterone
was necessary to correct a hormone imbalance is now losing
ground. Progesterone has been given orally, vaginally,
and rectally, in continuous and luteal phase regimens.
However, systematic reviews have found no convincing evidence
to support its use.