Pharmacodynamics and pharmacokinetics
Medroxyprogesterone acetate (MPA) is a progesterone derivative that does not have estrogenic activity and is classified as a gestagen (progestin). The androgenic activity of the compound is minimized. MPA in therapeutic doses reduces the production of pituitary gonadotropins, preventing the maturation of follicles and causing an anovulatory state in women of reproductive age. This effect leads to a decrease in the severity of vasomotor symptoms in menopausal women. MPA also increases the viscosity of cervical mucus, which accumulates in the cervical canal, as a result of which sperm penetration becomes almost impossible.
In some cases, an anabolic effect and anti-inflammatory effect of the drug are noted. In large doses it is characterized by glucocorticosteroid activity.
After intramuscular administration of medroxyprogesterone acetate, it is released quite slowly, which causes a low but constant level of MPA in the blood plasma. The maximum concentration of the substance after injection is reached after approximately 4–20 days, after which the MPA content gradually decreases and is approximately 1 ng/ml over 2–3 months. However, the compound may be present in plasma even 7–9 months after intramuscular administration. About 90–95% of MPA is bound to proteins in blood plasma. The volume of distribution is 20±3 l.
Medroxyprogesterone acetate penetrates the placental and blood-brain barriers, as well as into breast milk. The half-life averages 6 weeks. MPA is metabolized in the liver and eliminated primarily through biliary secretion through the intestine. Approximately 44% of MPA unchanged is excreted through the kidneys. More than 10 metabolites of the compound are known, excreted in the urine, mostly in the form of conjugates.
Rice. 3. Syncro-Mate-C subcutaneous system
In implantation systems of hormonal depot preparations
osmotically activated, the solution of the active substance is placed in a flexible, compressible, impermeable polyester capsule, the outer surface of which is in contact with the osmotically active substance, for example, sodium chloride. This system is covered on the outside with a semi-permeable membrane (Fig. 4).
After implantation, tissue fluid penetrates at a certain speed through the semi-permeable membrane and dissolves the osmotically active agent, thereby creating pressure on the flexible internal capsule. In this case, the solution of the active pharmaceutical ingredient, passing through the flow regulator at a given speed, enters the tissue. Depending on the concentration of the active ingredient, the therapeutic effect lasts from 1 to 4 weeks.
Instructions for use of Depo-Provera: method and dosage
In the treatment of breast cancer, the drug is used intramuscularly. The initial daily dosage of Depo-Provera is 500 mg, course duration is 28 days. At the end of this period, they switch to the use of maintenance doses - 2 times a week, 500 mg. Therapy should be continued until signs of disease regression appear.
In the treatment of kidney cancer, the drug is administered intramuscularly at an initial dose of 400-1000 mg per week. If the condition improves and stabilizes over several weeks or months, maintenance therapy is prescribed at 400 mg per month.
Immediately before use, the bottle should be shaken well (the administered drug should take the form of a homogeneous suspension).
Is there any point in trying?
Since no antidote has been developed against Depo-Provera, some women are wary of using the drug because of its irreversible effect within 3 months. And there are requests to do a test injection with a half dose, keeping in mind that then the product will have a validity period of one and a half months. It won't work that way.
A half dose simply does not work as a contraceptive. The introduction of 50 ml of the product instead of the prescribed 100 ml will not inhibit ovulation and thickening of mucus on the cervix, even for a period of less than one third of the normal three months.
Side effects
During therapy, it is possible to develop disorders of some body systems:
- Reproductive system: galactorrhea, dysfunctional uterine bleeding, amenorrhea, bleeding from the genital tract, breast tenderness, decreased libido or anorgasmia, vaginitis, hot flashes, leucorrhoea, lower abdominal pain;
- Digestive system: nausea, discomfort or pain in the abdomen, flatulence;
- Musculoskeletal system: joint and back pain, calf muscle cramps;
- Blood coagulation system: thrombophlebitis, thromboembolism;
- Central nervous system: dizziness, insomnia, increased nervous excitability, drowsiness, depression, fatigue, headache;
- Dermatological reactions: acne, rash, itching, alopecia and hirsutism;
- Allergic reactions: anaphylaxis and anaphylactoid reactions, urticaria;
- Other: hyperthermia, asthenia, moon face and changes in body weight.
special instructions
Before starting treatment, it is necessary to conduct a thorough examination of the patient.
If symptoms of thromboembolism develop, the benefit-risk ratio should be assessed before continuing therapy.
When using medroxyprogesterone acetate in high doses in cases of development of the Cushing's symptom complex (fluid retention, moon face, decreased glucose tolerance, increased blood pressure), it is necessary to reduce the dose if possible and carefully monitor the patient's condition. Also, the use of high doses of the drug can lead to weight gain and the development of fluid retention, as a result of which caution must be exercised during treatment of patients whose condition may be adversely affected by these disorders.
It is necessary to carefully monitor the condition of patients who have a history of treatment for depressive conditions, since when using medroxyprogesterone acetate, some patients complained of depression similar to premenstrual depression.
When conducting histological or cytological studies of the endometrium or cervix, the histologist must be warned about the therapy being carried out.
According to the instructions, Depo-Provera should be used with caution in the postpartum period, as this is associated with an increased risk of prolonged and heavy uterine bleeding.
It is believed that the therapy may increase the risk of developing osteoporosis.
The use of the drug should be discontinued in case of sudden partial or complete loss of vision, as well as in cases of double vision, bulging eyes, or migraine attacks. If during the examination swelling of the optic nerve nipple or damage to the fiber vessels is detected, the drug should not be prescribed.
If jaundice develops, the drug should be discontinued.
The use of Depo-Provera can increase the values of liver function indicators, change the results of the test for prothrombin (factor II) and blood clotting factors VII, VIII, IX, X (increasing), and also affect the results of the following laboratory tests:
- Determination of the levels of cortisol, progesterone, estrogens in the blood plasma (downward);
- Determination of gonadotropin levels (downwards);
- Determination of testosterone levels in blood plasma (downwards);
- Determination of the level of pregnanediol in urine (downwards);
- Carrying out a sugar load test (glucose tolerance test);
- Determination of the level of specific globulin that binds sex hormones (downwards);
- Metapyrone test.
Rice. 4. Implantation systems that are activated by an osmotic mechanism
- API solution that is released into tissue
- Removable flange cap
- Flange
- Stopper seal
- Flexible non-penetrating capsule
- Osmotically active substance
- Semi-permeable membrane
- Tissue fluid
- API reservoir
Similar in principle of operation are depot preparations activated by saturated steam pressure. These systems contain chambers containing a solution of the active pharmaceutical ingredient and a highly volatile liquid, separated from each other by a movable corrugated membrane. An inert volatile component, for example, a fluorocarbon, boils at body temperature; its vapor creates pressure on a movable membrane, which reduces the size of the chamber with the active substance, displacing it at a given speed into the surrounding tissues (Fig. 5).
Use during pregnancy and lactation
Pregnancy is a contraindication to the use of Depo-Provera, since under certain conditions a connection has been identified between taking progestogens in the first trimester of pregnancy and fetal development abnormalities.
In case of unplanned pregnancy that occurs within 1–2 months after intramuscular administration of MPA, the risk of malnutrition in newborns increases, which increases the risk of intrapartum and neonatal mortality. Such complications are uncommon, since conception occurs rarely during the use of MPA. If pregnancy occurs immediately after the administration of MPA, the woman should be warned about the possible risks to the fetus.
MPA passes into breast milk. There is no evidence that this may be harmful to a breastfed infant, but it is not recommended to prescribe Depo-Provera during the first 6 weeks of the postpartum period.
Disadvantages of the drug
The main complaints from patients using Depo-Provera:
Gaining excess weight
Moreover, this increase is not due to water retention in the body, associated with some dysfunction of the urinary system, but to a simple increased appetite.
After all, the main consumers of this long-acting hormonal contraceptive are young (25-35 years old) women of fertile age who have an active sex life, are actively building their careers, and for whom an unplanned pregnancy can serve as a life brake. For whom sex is not only pleasure, but also a way of communication, establishing connections (even business ones). And for them, weight gain, like the eternal desire to “eat something,” becomes a problem of appearance, extra effort and wasting time on diets and going to the gym. And the weight gain over a year of using the drug reaches at least one kilogram!
Delayed return of fertility
The fact is that the normalization of the menstrual cycle occurs after 9 months only even after not the last date of injection, but after the date that should follow the last one. That is, almost a year after stopping protection with Depo-Provera.
If a woman has a desire to have a child, then such long-term planning, regardless of life circumstances, is not always possible. Although this is only a matter of time, the use of the drug does not cause irreversible consequences, such cases are unknown to medicine.
Cycle disruption
Like other forms of progestogen contraceptives, Depo-Provera disrupts the cyclic sequence of menstruation, although the woman is warned about this in advance, otherwise cases of refusal of the drug would be frequent. In practice, most users of the product notice an increase in the incidence of minor bleeding and spotting. However, not in the quantities that require special thick menstrual pads with a high absorbency coefficient. After two or three injections are given (which means 6-9 months of walking under the influence of the drug), the cycle returns to normal.
But here another possible phenomenon begins to scare many: after the third injection, amenorrhea may occur - a complete absence of menstruation. Which, after all, are perceived by women as the norm of the female body, and their absence always indicated either the onset of pregnancy, or the onset of a serious gynecological (or even venereal!) disease.
However, timely explanatory work makes people reconciled with the absence of menstruation; women even find it convenient. Statistics say that approximately a third of those who use the product by injection develop a regular cycle by the end of the first year of using Provera, the second third develop amenorrhea, and the rest experience periodic bleeding not tied to any schedule. They can occur from overexcitation (including sexual) and from stress caused by any kind of emotions.
The picture changes dramatically after five years of using the drug: the number of women with regular cycles drops to 18%. In 3% of patients, irregular, weak bleeding persists, with breaks of up to 2-3 months, while the remaining approximately 80% develop amenorrhea.
Other unpleasant symptoms worthy of mention include vaginal dryness, decreased libido, unpleasant or even painful sensations in the mammary glands, and increased fatigue.
Reviews of Depo-Provera
Most often, reviews of Depo-Provera concern its use by women as a means of contraception. Many of them note that taking 150 mg of the drug once every 3 months turned out to be really effective in preventing conception. However, in many cases of using the drug, various side effects are observed, for example, weight gain.
Doctors have different opinions regarding medroxyprogesterone acetate. Some of them recommend using it for all their patients, while other experts believe that the drug is more suitable for older women. There are numerous reviews indicating that the administration of Depo-Provera can cause complications in subsequent pregnancies or make it difficult to conceive even after a long time.
Some people even administer Depo-Provera to cats, using it as a form of contraception. However, the consequences can be severe: experienced breeders claim that 90% of animals remain sterile after using the drug.
