Provera: composition and presentation
One tablet contains 5 mg or 10 mg of medroxyprogesterone acetate. Two strengths are needed because the medicine has four indications, and almost each of them has its own dosing scheme.
The composition includes lactose, so the medicine is not prescribed in the rare hereditary galactose intolerance, Lapp lactase deficiency or glucose and galactose malabsorption syndrome. No systematic observations have been made of its influence on the ability to drive and to operate machinery.
How Provera works
Medroxyprogesterone acetate is a synthetic progestin molecule, close in structure to the body's own progesterone. Its action on the endocrine system is made up of several proven effects, the first being inhibition of the secretion of the pituitary gonadotropins, follicle-stimulating and luteinising hormone.
After that the chain branches. The medicine reduces the blood levels of adrenocorticotropic hormone and hydrocortisone, lowers the concentration of testosterone in peripheral blood, and reduces the concentration of oestrogens. The last of these happens by two routes at once: through inhibition of follicle-stimulating hormone, and through induction of a hepatic reductase, which raises testosterone clearance so that fewer androgens are converted into oestrogens. The fall in oestrogens is not an incidental detail but the reason for a separate warning about bone density, to which we return below.
Indications
There are four indications and they are of different kinds: secondary amenorrhoea; functional, that is anovulatory, uterine bleeding caused by hormonal imbalance; mild to moderate endometriosis.
The fourth stands apart — countering endometrial growth in women taking oestrogens. Here the medicine does not treat a symptom but protects the lining of the uterus from what oestrogen therapy does to it. Hence the rule: progestogens are not recommended for women whose uterus has been removed — except where endometriosis has been diagnosed. In all four situations the active substance is the same, but its task differs: in one case to bring on withdrawal bleeding, in another to halt growth of the lining, in a third to suppress endometriosis foci. That is why the schemes differ not by percentages but several times over.
Method of use and dosage
The scheme depends on the indication, and the differences between them are large: from five days of tablets to ninety in a row. The general principle for hormone therapy of menopausal symptoms is set out separately — the lowest effective dose for the shortest time, together with periodic examinations whose type and frequency are decided by the patient's condition.
| Indication | Scheme |
| Secondary amenorrhoea | 5–10 mg a day for 5–10 days; bleeding should occur within 3–7 days of stopping |
| Functional uterine bleeding | 5–10 mg a day for 5–10 days, starting around day 16–21 of the cycle; bleeding is expected 3–7 days after stopping |
| Repeating the course in bleeding | the same dose may be repeated starting on day 16 of the cycle for 2–3 consecutive cycles, after which treatment is interrupted to see whether the functional disturbance has resolved |
| Mild to moderate endometriosis | 10 mg three times a day for 90 consecutive days, starting on the first day of the menstrual cycle |
| Endometrial protection, continuous scheme | 2.5–5 mg a day |
| Endometrial protection, sequential scheme | 5–10 mg a day for 10–14 consecutive days of a 28-day cycle |
To two of the schemes the leaflet adds the figures to expect, and they are useful as a guide. In treating endometriosis, 30–40% of patients have self-limiting spotting — in that case no additional hormone therapy is recommended. In endometrial protection, withdrawal bleeding or spotting occurs in 75–80% of women, so it is an expected event rather than a sign of failure.
Contraindications
The first group is pregnancy and everything connected with it: pregnancy or suspicion of it, use in the diagnosis of pregnancy, and missed abortion. Hypersensitivity to medroxyprogesterone acetate or to any excipient belongs here too.
The remaining contraindications concern the vessels, the liver and tumours. Caution is noted separately where there is known hypersensitivity to steroids other than medroxyprogesterone acetate: a cross-reaction is possible here, although such hypersensitivity is not a formal contraindication.
- bleeding from the genital or urinary tract of unestablished cause;
- venous thrombotic disease;
- stroke in the history;
- severe liver failure;
- diagnosed or suspected malignant tumour of the breast or of a genital organ.
Special warnings and precautions
Let us start with a rule worth remembering word for word. If a patient suddenly suffers partial or complete loss of vision, or if proptosis, double vision or migraine appear suddenly, the medicine is stopped and a thorough ophthalmological examination is carried out. If papilloedema or changes in the retinal vessels are found, treatment is not continued. The second rule is simpler: any unexpected genital bleeding that occurs during treatment must be investigated, not waited out.
- medroxyprogesterone acetate causes fluid retention to a greater or lesser degree, so caution is needed in epilepsy, migraine, asthma and disorders of heart or kidney function — wherever weight gain or fluid retention could worsen the condition;
- patients with depression in the history are watched carefully during treatment, and in some women manifestations corresponding to premenstrual depression appear;
- in some people glucose tolerance falls, so patients with diabetes are observed especially closely;
- the medicine does not, on the available data, cause thrombotic or thromboembolic disorders, but with such disorders in the history it is not recommended, and if venous thromboembolism develops during treatment it is stopped;
- if a specimen of the lining of the uterine body or of the cervical canal is sent for histopathological examination, the laboratory is told that the medicine is being taken: it can lower the concentrations of hormonal biomarkers — steroids in plasma and urine, gonadotropins, and sex hormone binding globulin.
Before any hormone therapy is started, a full history is taken, the family history included. Examination before treatment and periodically after it begins should cover above all blood pressure measurement, examination of the breasts, abdomen and pelvic organs, and cervical cytology — that list is worth keeping in mind when planning the visit. Bone density is a separate topic, and it follows from the mechanism of action. Density studies did not concern the tablets taken by mouth, but with intramuscular administration of 150 mg every three months as a contraceptive method, after five years the mean density of the lumbar spine fell by 5.4%, and over the two years after stopping it partly returned towards baseline. Since a fall in oestrogens can reduce bone density in premenopausal women and increase the risk of osteoporosis later in life, all patients are advised to take calcium and vitamin D in appropriate doses, and with long-term use an assessment of bone mineral density is sometimes indicated. The leaflet also warns outright: oestrogens alone or together with progestogens are not used to prevent cardiovascular disease. In the part of the WHI study devoted to conjugated oestrogens combined with medroxyprogesterone acetate, cardiovascular events from coronary heart disease occurred more often than on placebo — 37 against 30 per 10 000 person-years — and the rate of venous thromboembolism was twice as high in the first year alone. The same study found a rise in breast cancer risk that grew with the duration of use, a greater number of abnormal mammograms requiring further evaluation, and an increased risk of manifestations consistent with dementia in women aged 65 and over.
Interactions with other medicines
Few interactions are described for this medicine, and the first is specific: giving aminoglutethimide together with high doses of medroxyprogesterone acetate can significantly lower its plasma concentration and weaken its action.
The second concerns laboratory diagnosis: the medicine may affect the results of the metyrapone test. As for enzymes, outside the body medroxyprogesterone acetate is metabolised mainly by hydroxylation involving CYP3A4, but detailed studies of the clinical consequences of combining it with inducers or inhibitors of that enzyme have not been carried out — so the clinical effects of such combinations are unknown. That is an honest statement of uncertainty, and it is worth treating as grounds for caution rather than as permission.
Pregnancy and breastfeeding
In pregnancy the medicine is contraindicated. There is data pointing to a link between taking medicines of the progestogen group in the first trimester and developmental disorders of the genital system in fetuses of both sexes.
The patient is therefore warned of the possible risk to the fetus if medroxyprogesterone acetate is used during pregnancy, or if pregnancy occurs while it is being taken. The medicine itself and its metabolites pass into human milk; there is no evidence that this poses any risk to a breastfed child, but use during breastfeeding is nonetheless not recommended.
Adverse reactions
Very commonly there are headache, nausea and abnormal uterine bleeding — irregular, excessively heavy or too scant. Common are hypersensitivity to the medicine, depression, insomnia, nervousness, dizziness, and also hair loss, acne, urticaria and itching.
Uncommonly there is excess hair growth. With unknown frequency anaphylactic and anaphylactoid reactions, angioneurotic oedema, a prolonged period without ovulation, drowsiness, embolism and thromboembolic disorders, jaundice including the cholestatic form, acquired lipodystrophy and rash have been reported. Note how two lines sit side by side: irregular bleeding is among the commonest events, and yet every unexpected bleed calls for its cause to be established — the familiarity of a symptom does not remove the need to investigate it.
Overdose
Oral doses of up to 3 g a day were well tolerated. That is markedly more than any therapeutic dose: even in endometriosis the daily dose is 30 mg.
Treatment of overdose is symptomatic and supportive; the leaflet provides for no specific measures.
How to get a Provera prescription online
The medicine is available on prescription, and what will shape the conversation with the doctor first is what it is being prescribed for. The schemes for amenorrhoea, functional bleeding, endometriosis and endometrial protection differ both in dose and in length, so it is worth describing straight away what is happening: how long there has been no period, how heavy the bleeding is and which days of the cycle it falls on, whether you take oestrogens and whether the uterus has been removed.
For the online consultation prepare information about pregnancy and its possibility, about thromboses and any stroke you have had, about liver disease, about breast and genital tumours in yourself and in close female relatives, about depression, diabetes, epilepsy, migraine, asthma and heart and kidney disease. The date of your last cervical smear and the results of a recent examination, blood pressure included, will be useful. List the medicines you take, aminoglutethimide among them. The doctor will assess these circumstances and, if there are no contraindications, will issue an electronic prescription.
