ALLYLOESTRENOL
Allyloestrenol is a progesterone structurally related to progesterone
that has been given in threatened abortion and habitual abortion,and to
prevent premature labour.However,with the exception of proven
progesterone deficiency,such use is no longer recommended.In threatened
abortion in progesterone deficient women a suggested dose is 5 mg three
times daily by mouth for 5-7 days.
For full details of progesterone see progesterone record below :
PROGESTERONE
DESCRIPTION
ORGAGEST® (progesterone, USP) Capsules contain micronized progesterone for oral administration. Progesterone has a molecular weight of 314.47 and an empirical formula of C 21 H 30 O 2 . Progesterone (pregn-4-ene-3, 20-dione) is a white or creamy white, odorless, crystalline powder practically insoluble in water, soluble in alcohol, acetone and dioxane and sparingly soluble in vegetable oils, stable in air, melting between 126° and 131°C.
Progesterone is synthesized from a starting material from a plant source and is chemically identical to progesterone of human ovarian origin.
CLINICAL PHARMACOLOGY
ORGAGEST Capsules are an oral dosage form of micronized progesterone which is chemically identical to progesterone of ovarian origin. The oral bioavailability of progesterone is increased through micronization.
Pharmacokinetics
Absorption
After oral administration of progesterone as a micronized soft gelatin capsule formulation, maximum serum concentrations were attained within 3 hours. The absolute bioavailability of micronized progesterone is not known.
Serum progesterone concentrations appeared linear and dose proportional following multiple dose administration of ORGAGEST Capsules 100 mg over the dose range 100 mg/day to 300 mg/day in postmenopausal women. Although doses greater than 300 mg/day were not studied in females, serum concentrations from a study in male volunteers appeared linear and dose proportional between 100 mg/day and 400 mg/day. The pharmacokinetic parameters in male volunteers were generally consistent with those seen in postmenopausal women.
Distribution
Progesterone is approximately 96%-99% bound to serum proteins, primarily to serum albumin (50%-54%) and transcortin (43%-48%).
Metabolism
Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites which are excreted in the bile may be deconjugated and may be further metabolized in the gut via reduction, dehydroxylation, and epimerization.
Excretion
The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the bile and urine. Progesterone metabolites which are excreted in the bile may undergo enterohepatic recycling or may be excreted in the feces.
Special Populations
The pharmacokinetics of ORGAGEST Capsules have not been assessed in low body weight or obese patients.
Race:
There is insufficient information available from trials conducted with ORGAGEST Capsules to compare progesterone pharmacokinetics in different racial groups.
Hepatic Insufficiency:
No formal studies have evaluated the effect of hepatic disease on the disposition of progesterone. However, since progesterone is metabolized by the liver, use in patients with severe liver dysfunction or disease is contraindicated (see CONTRAINDICATIONS ). If treatment with progesterone is indicated in patients with mild to moderate hepatic dysfunction, these patients should be monitored carefully.
Renal Insufficiency:
No formal studies have evaluated the effect of renal disease on the disposition of progesterone. Since progesterone metabolites are eliminated mainly by the kidneys, ORGAGEST Capsules should be used with caution and only with careful monitoring in patients with renal dysfunction. (see PRECAUTIONS )
Food-Drug Interaction:
Concomitant food ingestion increased the bioavailability of ORGAGEST Capsules relative to a fasting state when administered to postmenopausal women at a dose of 200 mg.
Drug-Drug Interaction:
The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC 50 <0.1 µM). Ketoconazole is a known inhibitor of cytochrome P450 3A4, hence these data suggest that ketoconazole or other known inhibitors of this enzyme may increase the bioavailability of progesterone. The clinical relevance of the in vitro findings is unknown.
Coadministration of conjugated estrogens and ORGAGEST Capsules to 29 postmenopausal women over a 12 day period resulted in an increase in total estrone concentrations (Cmax 3.68 ng/ml to 4.93 ng/ml) and total equilin concentrations (Cmax 2.27 ng/ml to 3.22 ng/ml) and a decrease in circulating 17(beta) estradiol concentrations (Cmax 0.037 ng/ml to 0.030 ng/ml). The half-life of the conjugated estrogens was similar with coadministration of ORGAGEST Capsules.
Clinical Studies
Endometrial Protection
In a randomized double-blind clinical trial, 358 postmenopausal women, each with an intact uterus, received treatment for up to 36 months. The treatment groups were: ORGAGEST Capsules at the dose of 200 mg/day for 12 days per 28 day cycle in combination with conjugated estrogens 0.625 mg/day (n=120); conjugated estrogens 0.625 mg/day only (n=119); or placebo (n=119). The subjects in all three treatment groups were primarily Caucasian women (87% or more of each group). The results for the incidence of endometrial hyperplasia in women receiving up to 3 years of treatment are shown in Table 3. A comparison of the ORGAGEST Capsules plus conjugated estrogens treatment group to the conjugated estrogens only group showed a significantly lower rate of hyperplasia (6% combination product vs. 64% estrogen alone) in the ORGAGEST Capsules plus conjugated estrogens treatment group throughout 36 months of treatment.
Table 3 Incidence of Endometrial Hyperplasia in Women
Receiving 3 Years of Treatment
Endometrial Diagnosis Treatment Group
Conjugated Estrogens Conjugated Estrogens Placebo Number of Number of Number of
0.625 mg+ ORGAGEST 0.625 mg (only) Patients % of Patients % of Patients % of
Capsules 200 mg Patients Patients Patients
(cyclical)
N=117 N=115 N=116
Hyperplasia a 7 6 74 64 3 3
Adenocarcinoma 0 0 0 0 1 1
Atypical hyperplasia 1 1 14 12 0 0
Complex hyperplasia 0 0 27 23 1 1
Simple hyperplasia 6 5 33 29 1 1
a Most advanced result to least advanced result: Adenocarcinoma > atypical hyperplasia > complex hyperplasia > simple hyperplasia
The times to diagnosis of endometrial hyperplasia over 36 months of treatment are shown in Figure 1. This figure illustrates graphically that the proportion of patients with hyperplasia was significantly greater for the conjugated estrogens group (64%) compared to the conjugated estrogens plus ORGAGEST Capsules group (6%).
The discontinuation rates due to hyperplasia over the 36 months of treatment are as shown in Table 4. For any degree of hyperplasia, the discontinuation rate for patients who received conjugated estrogens plus ORGAGEST Capsules was similar to that of the placebo only group, while the discontinuation rate for patients who received conjugated estrogens alone was significantly higher. Women who permanently discontinued treatment due to hyperplasia were similar in demographics to the overall study population.
In the same three year clinical trial, postmenopausal women were treated with ORGAGEST Capsules in combination with conjugated estrogens, conjugated estrogens only, or placebo. There was no statistically significant difference between the ORGAGEST Capsules plus conjugated estrogens group and the conjugated estrogens only group in increases of HDL-C and triglycerides, or in decreases of LDL-C.
Secondary Amenorrhea
In a single-center, randomized, double-blind clinical study that included premenopausal women with secondary amenorrhea for at least 90 days, administration of 10 days of ORGAGEST Capsules therapy resulted in 80% of women experiencing withdrawal bleeding within 7 days of the last dose of ORGAGEST Capsules, 300 mg/day (n=20), compared to 10% of women experiencing withdrawal bleeding in the placebo group (n=21).
The rate of secretory transformation was evaluated in a multicenter, randomized, double-blind clinical study in estrogen-primed postmenopausal women. ORGAGEST Capsules administered orally for 10 days at 400 mg/day (n=22) induced complete secretory changes in the endometrium in 45% of women compared to 0% in the placebo group (n=23).
INDICATIONS AND USAGE
ORGAGEST Capsules are indicated for use in the prevention of endometrial hyperplasia in non-hysterectomized postmenopausal women who are receiving conjugated estrogens tablets. They are also indicated for use in secondary amenorrhea.
CONTRAINDICATIONS
Known sensitivity to ORGAGEST Capsules or its ingredients. ORGAGEST Capsules contain peanut oil and should never be used by patients allergic to peanuts.
Known or suspected pregnancy.
Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or patients with a past history of these conditions.
Severe liver dysfunction or disease.
Known or suspected malignancy of breast or genital organs.
Undiagnosed vaginal bleeding.
Missed abortion.
As a diagnostic test for pregnancy.
WARNINGS
The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately.
Discontinue medication pending examination if there is sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn.
The administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. Detectable amounts of progestin have been identified in the milk of mothers receiving progestins. The effect of this on the nursing infant has not been determined.
Retrospective studies of morbidity and mortality in Great Britain and studies of morbidity in the United States have shown a statistically significant association between thrombophlebitis, pulmonary embolism, cerebral thrombosis and embolism, and the use of oral contraceptives. The estimate of the relative risk of thromboembolism in the study by Vessey and Doll was about seven fold, while Sartwell and associates in the United States found a relative risk of 4.4, meaning that the users are several times as likely to undergo thromboembolic disease without evident cause as nonusers. The American study also indicated that the risk did not persist after discontinuation of administration, and that it was not enhanced by long-continued administration. The American study was not designed to evaluate a difference between products.
PRECAUTIONS
General
The pretreatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear.
Because progesterone may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation.
In cases of breakthrough bleeding, as in any cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated.
Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.
Any possible influence of prolonged progestin therapy on pituitary, ovarian, adrenal, hepatic or uterine functions awaits further study.
Although concomitant use of conjugated estrogens and ORGAGEST Capsules did not result in a decrease in glucose tolerance, diabetic patients should be carefully observed while receiving estrogen-progestin therapy.
The pathologist should be advised of progestin therapy when relevant specimens are submitted.
Because of the occurrence of thrombotic disorders (thrombophlebitis, pulmonary embolism, retinal thrombosis, and cerebrovascular disorders) in patients taking estrogen-progestin combinations, the physician should be alert to the earliest manifestation of these disorders.
Transient dizziness may occur in some patients. Use caution when driving a motor vehicle or operating machinery. A small percentage of women may experience extreme dizziness and/or drowsiness during initial therapy. For these women, bedtime dosing is advised.
Information for the Patient
See accompanying Patient Insert.
General: This product contains peanut oil and should not be used if you are allergic to peanuts.
Drug Lab Test Interactions
The following laboratory results may be altered by the use of estrogen-progestin combination drugs:
Increased sulfobromophthalein retention and other hepatic function tests.
Coagulation tests: increase in prothrombin factors VII, VIII, IX and X.
Metyrapone test.
Pregnanediol determination.
Thyroid function: increase in PBI, and butanol extractable protein bound iodine and decrease in T3 uptake values.
Fasting and 2-hour plasma insulin and glucose levels following an oral glucose tolerance test (OGTT) and fibrinogen levels were measured in patients receiving ORGAGEST Capsules at a dose of 200 mg/day for 12 days per 28 day cycle in combination with conjugated estrogens 0.625 mg/day (n=120). Table 6 summarizes this data. Plasma insulin levels 2 hours post-OGTT were decreased from baseline. The fasting plasma glucose and fasting plasma insulin levels were also decreased from baseline. Glucose levels 2 hours post-OGTT were increased slightly. There was no effect on fibrinogen levels.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Progesterone has not been tested for carcinogenicity in animals by the oral route of administration. When implanted into female mice, progesterone produced mammary carcinomas, ovarian granulosa cell tumors and endometrial stromal sarcomas (1). In dogs, long-term intramuscular injections produced nodular hyperplasia and benign and malignant mammary tumors (2). Subcutaneous or intramuscular injections of progesterone decreased the latency period and increased the incidence of mammary tumors in rats previously treated with a chemical carcinogen (3).
Progesterone did not show evidence of genotoxicity in in vitro studies for point mutations or for chromosomal damage. In vivo studies for chromosome damage have yielded positive results in mice at oral doses of 1000 mg/kg and 2000 mg/kg (4). Exogenously administered progesterone has been shown to inhibit ovulation in a number of species and it is expected that high doses given for an extended duration would impair fertility until the cessation of treatment.
Pregnancy Category B
Reproductive studies have been performed in mice at doses up to 9 times the human oral dose (5, 6), in rats at doses up to 44 times the human oral dose (7, 8), in rabbits at a dose of 10 µg/day delivered locally within the uterus by an implanted device (9), in guinea pigs at doses of approximately one-half the human oral dose (10) and in rhesus monkeys (11) at doses approximately the human dose, all based on body surface area, and have revealed little or no evidence of impaired fertility or harm to the fetus due to progesterone.
Several studies in women exposed to progesterone have not demonstrated any significant increase in fetal malformations (12). A single case of cleft palate was observed in the child of a woman using ORGAGEST Capsules in early pregnancy, although definitive causality has not been established. Rare instances of fetal death have been reported in pregnant women prescribed ORGAGEST Capsules for unapproved indications. Because the studies in humans cannot rule out the possibility of harm, ORGAGEST Capsules should be used during pregnancy only if indicated (see CONTRAINDICATIONS ).
Nursing Mothers
The administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. Detectable amounts of progestin have been identified in the milk of nursing mothers receiving progestins. The effect of this on the nursing infant has not been determined.
Pediatric Use
The safety and effectiveness of ORGAGEST Capsules in pediatric patients have not been established.
ADVERSE REACTIONS
Endometrial Protection
Table 7 lists adverse experiences which were reported in >/=2% of patients (regardless of relationship to treatment) who received cyclic ORGAGEST Capsules, 200 mg daily (12 days per calendar month cycle) with daily 0.625 mg conjugated estrogen, in a multicenter, randomized, double-blind, placebo-controlled clinical trial in 875 postmenopausal women.
Table 7 Adverse Experiences (>/=2%) Reported in an 875 Patient Placebo-Controlled Trial in
Postmenopausal Women over a 3-Year Period (Percentage (%) of Patients Reporting)
ORGAGEST Capsules Conjugated Estrogens Placebo
200 mg with 0.625 mg (only)
Conjugated Estrogens
0.625 mg
(N=178) (N=175) (N=174)
Headache 31 30 27
Breast Tenderness 27 16 6
Joint Pain 20 22 29
Depression 19 18 12
Dizziness 15 5 9
Abdominal Bloating 12 10 5
Hot Flashes 11 14 35
Urinary Problems 11 10 9
Abdominal Pain 10 13 10
Vaginal Discharge 10 10 3
Nausea/Vomiting 8 6 7
Worry 8 5 4
Chest Pain 7 4 5
Diarrhea 7 7 4
Night Sweats 7 5 17
Breast Pain 6 6 2
Swelling of Hands and Feet 6 9 9
Vaginal Dryness 6 8 10
Constipation 3 3 2
Breast Carcinoma 2 <1 <1
Breast Excisional Biopsy 2 1 <1
Cholecystectomy 2 <1 <1
Secondary Amenorrhea
Table 8 lists adverse experiences which were reported in >/=5% of patients receiving ORGAGEST Capsules, 400 mg/day, in a multicenter, randomized, double-blind, placebo-controlled clinical trial in estrogen-primed (6 weeks) postmenopausal women receiving conjugated estrogens 0.625 mg/day and cyclic (10 days per calendar month cycle) ORGAGEST Capsules at a dose of 400 mg/day, for three cycles.
Table 8 Adverse Experiences (>/=5%) Reported in Patients Using 400 mg/day in a
Placebo-Controlled Trial in Estrogen-Primed Postmenopausal Women
Adverse Experience
ORGAGEST Capsules 400 mg Placebo
N=25 N=24
Percentage (%) of Patients
Fatigue 8 4
Headache 16 8
Dizziness 24 4
Abdominal Distention (Bloating) 8 8
Abdominal Pain (Cramping) 20 13
Diarrhea 8 4
Nausea 8 0
Back Pain 8 8
Musculoskeletal Pain 12 4
Irritability 8 4
Breast Pain 16 8
Infection Viral 12 0
Coughing 8 0
The most common adverse experiences reported in >/=5% of patients in all ORGAGEST Capsules dosage groups studied in this trial (100 mg/day to 400 mg/day) were: dizziness (16%), breast pain (11%), headache (10%), abdominal pain (10%), fatigue (9%), viral infection (7%), abdominal distention (6%), musculoskeletal pain (6%), emotional lability (6%), irritability (5%), and upper respiratory tract infection (5%).
Other adverse events reported in <5% of patients taking ORGAGEST Capsules include:
Autonomic Nervous System Disorders: dry mouth
Body As A Whole: accidental injury, chest pain, fever
Cardiovascular System Disorders: hypertension
Central and Peripheral Nervous System Disorders: confusion, somnolence, speech disorder
Gastrointestinal System Disorders: constipation, dyspepsia, gastroenteritis, hemorrhagic rectum, hiatus hernia, vomiting
Hearing and Vestibular Disorders: earache
Heart Rate and Rhythm Disorders: palpitation
Metabolic and Nutritional Disorders: edema, edema peripheral
Musculoskeletal System Disorders: arthritis, leg cramps, hypertonia, muscle disorder, myalgia
Myo/Endo/Pericardial and Valve Disorders: angina pectoris
Psychiatric Disorders: anxiety, impaired concentration, insomnia, personality disorder
Reproductive System Disorders: leukorrhea, uterine fibroid, vaginal dryness, fungal vaginitis, vaginitis
Resistance Mechanism Disorders: abscess, herpes simplex
Respiratory System Disorders: bronchitis, nasal congestion, pharyngitis, pneumonitis, sinusitis
Skin and Appendages Disorders: acne, verruca, wound debridement
Urinary System Disorders: urinary tract infection
Vision Disorders: abnormal vision
White Cell and Resistance Disorders: lymphadenopathy
The following adverse experiences have been reported with ORGAGEST Capsules in other U.S. clinical trials: increased sweating, asthenia, tooth disorder, anorexia, increased appetite, nervousness, and breast enlargement.
The following spontaneous adverse events have been reported during the foreign marketing of ORGAGEST Capsules: reversible cases of hepatitis and elevated transaminases. These events occurred mainly in patients receiving high doses of up to 1200 mg.
The following additional adverse experiences have been observed in women taking progestins in general: breakthrough bleeding, spotting, change in menstrual flow, amenorrhea, changes in weight (increase or decrease), changes in the cervical squamo-columnar junction and cervical secretions, cholestatic jaundice, anaphylactoid reactions and anaphylaxis, rash (allergic) with and without pruritus, melasma or chloasma, pyrexia, and insomnia.
OVERDOSAGE
No studies on overdosage have been conducted in humans. In the case of overdosage, ORGAGEST Capsules should be discontinued, and the patient should be treated symptomatically.
DOSAGE AND ADMINISTRATION
Prevention of endometrial hyperplasia --ORGAGEST Capsules should be given as a single daily dose in the evening, 200 mg orally for 12 days sequentially per 28 day cycle, to postmenopausal women with a uterus who are receiving daily conjugated estrogens tablets.
Secondary Amenorrhea --ORGAGEST Capsules may be given as a single daily dose of 400 mg in the evening for 10 days.
Progesterone is a natural hormone whereas pro-
gestogens are synthetic compounds, derived from
progesterone or 19-nortestosterone, with actions
similar to those of progesterone.
Progestogens derived from 19-nortestosterone are
used as hgnnonal contraceptives, ei-
ther alone or combined with an oestrogen. The pro-
gesterone derivative medroxyprogesterone acetate is
also used, and progesterone itself has been used.
Both progesterone and 19-nortestosterone deriva-
tives are used in combination with oestrogens for
menopausal hormone replacement therapy to reduce the increased risk of endometrial hyperplasia and carcinoma which occurs when un-
opposed long-term oestrogen therapy is employed.
Progesterone itself is under investigation for such
use.
Progestogens, and sometimes progesterone may be
used in menstrual disorders such as dysmenor-
rhoea and menorrhagia associated with dys-
functional uterine bleeding. Progestogens
may also be used in the management of endometri-
osis. Although progestogens and proges-
terone have been used for the management of the
pre~enstrual syndrome, such a practice is of debat-
able value.
Progestogens may be valuable in endometrial can-
cer and have been tried in some other malig-
nancies. The progestogens typically used for
malignant disease include medroxyprogesterone ac-
etate, megestrol, and norethisterone. Some pro-
gestogens such as megestrol and
medroxyprogesterone are used for the cachexia or
wasting associated with severe illness including
cancer and AIDS.
Progestogens have been widely advocated for either
the prevention of habitual abortion or the treat-
ment of threatened abortion. However, many author-
ities now consider that there is little evidence of any
benefit from such a practice and recommend against
the use of progestogens in early pregnancy, with ex-
ception of the use of progesterone or a progesterone
derivative in women who are progesterone deficient
(see also under Precautions above).
USES AND ADMINISTRATION OF PROGESTERONE. Pro-
gesterone is usually administered as an oily intra-
muscular injection or as pessaries or suppositories.
An oral micronised preparation of progesterone is
under investigation for a variety of disorders, as is a
vaginal gel.
In dysfunctional uterine bleeding 5 to 10 mg daily of
progesterone is normally given by intramuscular in-
jection for about 5 to 10 days before the anticipated
onset of menstruation. A similar regimen has been
used in the treatment of amenorrhoea.
In women with a history of habitual abortion and
proven progesterone deficiency, twice weekly intra-
muscular injection (increased to daily if necessary)
of 25 to 100 mg of progesterone from approximate-
ly day 15 of the pregnancy until 8 to 16 weeks has
been used. A similar schedule has been used in in-
vitro fertilization or gamete intra-fallopian transfer
techniques with treatment beginning on the day of
transfer of embryo or gametes. The dose may be in-
creased to 200 mg daily if necessary.
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. Treat-
ment usually starts on day 12 to 14 of the menstrual
cycle and continues until the onset of menstruation.
Similar intravaginal or intrarectal doses have also
been used in the treatment of puerperal (post-natal)
depression.
A progesterone-releasing intra-uterine device has
also been used as a hormonal contraceptive; the de-
vice contains 38 mg of progesterone and is effective
for up to 12 months.
Menorrhagia. Menorrhagia or excessive menstrual bleed-
ing. 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 'flooding' occurs. Although not
life-threatening, menorrhagia can lead to iron deficiency
anaemia as well as considerably impairing quality of life.
Menonhagia may be a symptom of pelvic disorders such as
fibroids or endometriosis, or of systemic disorders such as hv-
pothyroidism or clotting defects, or be associated with the use
of copper intra-uterine devices. 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. In this situation, it may
be referred to as essential, idiopathic, or primary menor-
rhagia.
Dysfunctional uterine bleeding is thought to be associated
with abnormalities of prostaglandin production, and treat-
ment with NSAIDs such as ibuprofen, mefenamic acid or
naproxen is often employed. These reduce menstrual blood
loss by about 30%, and relieve dysmenorrhea . There
does not appear to be any evidence to suggest that any one
NSAID is more effective than any other. An alternative in
women who require contraception is a combined oral contra-
ceptive which appears to be as effective as an NSAID.
In women who are anaemic or who do not respond to NSAIDs
or oral contraceptives, or for whom these are not appropriate.
the antifibrinolytic tranexamic acid may be tried. When ad-
ministered during menstruation, it reduces blood loss by
about 50%. However, gastro-intestinal adverse effects are
common, and (as with combined oral contraceptives) it is
contra-indicated in women with thrombo-embolic disorders.
Ethamsylate has been reported to have similar efficacy to an
NSAID in I study, but to be ineffective in another.
More recently, a levonorgestrel-containing intra-uterine de-
vice has been shown to be very effective in reducing menstru-
al blood loss and to be an alternative to hysterectomy in
menorrhagia. It has been suggested that this may become the
preferred long-term medical treatment for menorrhagia.
Danazol is also effective, but has significant adverse effects
and treatment is usually limited to 3 to 6 months. Traditional
therapy with progestogens is of limited efficacy in menor-
rhagia occurring during ovulatory cycles. However it is suita-
ble for anovulatory bleeding; norethisterone.
medroxyprogesterone, or dydrogesterone have been suggest-
ed for such use. Gonadorelin analogues are effective for men-
orrhagia associated with fibroids, but can only be
used short term because of the resultant ovarian suppres-
sion.
In patients who fail to respond lo 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 appear to
be an effective alternative to hysterectomy. Hysterectomy
is the ultimate therapy, but is associated with significant mor-
bidity: given that menorrhagia is not life-threatening some
consider that hysterectomy has been overused.
Premenstrual syndrome. Progestogen therapy was once
popular for premenstrual syndrome, but beneficial responses
have not been universally achieved and the theory that pro-
gesterone was necessary to correct a hormone imbalance is
now losing ground. A double-blind, placebo-
controlled crossover study involving 168 women showed
that progesterone 0.4 or 0.8 g daily by the vaginal route did
not significantly improve symptoms of the premenstrual syn-
drome. However, the view has been expressed that since ab-
sorption of progesterone from the vagina or rectum may vary
between patients, the dose and frequency of administration
needs to be individualised and that if the response to treat-
ment is inadequate the intramuscular route should be tried. A
more recent study found oral micronised progesterone. in an
initial dose of 1.2 g daily in divided doses, increased as re-
quired to 3.6 g daily, to be no better than placebo in the man-
agement of severe premenstrual syndrome.