IVF is carried out under constant control, from patients visiting a doctor to achieving the goal - pregnancy through artificial insemination. For the result to be successful, the woman receives hormonal support. Before IVF, hormonal correction may be carried out to prepare the reproductive system for pregnancy. An analysis of the hormone estradiol must be carried out in advance and a transcript must be made. One of the hormone-containing drugs used in the complex of replacement therapy for IVF is Divigel . Hormone therapy is the most important stage of preparation; the expectant mother’s body must be completely ready to accept the embryo.
The task of doctors is to monitor the readiness of the woman’s reproductive system, on which the success of in vitro fertilization depends.
Directions for use and doses
Transdermal. Divigel can be used for long-term and cyclic therapy. The usual starting dose is 1.0 mg estradiol (1.0 g gel, respectively) per day, but the choice of starting dose may be based on the severity of symptoms. Depending on the clinical picture, the dose can be changed after 2-3 cycles individually from 0.5 to 1.5 g per day, which corresponds to 0.5 to 1.5 mg estradiol per day.
For patients with an intact (unoperated) uterus, during treatment with Divigel, it is recommended to prescribe a progestin (for example, medroxyprogesterone acetate, norethisterone, norethisterone acetate or dihydrogesterone) for 10-12 days in each cycle. After a course of gestagen, menstrual-like bleeding should occur. In case of extraordinary or prolonged uterine bleeding, the cause of its occurrence must be determined.
In postmenopausal patients, the cycle duration can be increased to 3 months.
The gel is usually applied once a day to clean skin of the lower part of the anterior abdominal wall, lumbar region, shoulders, forearms, or alternately to the right or left buttocks, alternating the application sites daily. The application area should be equal in size to 1–2 palms. After applying the drug, you should wait a few minutes until the gel dries (2-3 minutes). The area where the gel is applied should not be rinsed for 1 hour. Accidental contact of Divigel with the eyes should be avoided. You should wash your hands immediately after applying the gel.
If the patient has forgotten to apply the gel, this should be done as soon as possible, but no later than within 12 hours from the date of application of the drug as scheduled. If more than 12 hours have passed, then the application of Divigel should be postponed until the next time. If the drug is not used regularly (missed doses), menstrual-like uterine breakthrough bleeding may occur.
Description
The active component of Divigel is a gonadosteroid of the estrogen class - estradiol, whose chemical structure is close to estradiol produced by the ovaries. Divigel is effective in case of insufficient production of this hormone by the gonads, which is the most active among female steroids and is formed from testosterone during enzymatic processes.
The effect of estradiol on the female and male body is enormous:
- stimulation of the development of a woman’s reproductive organs (uterus, fallopian tubes), mammary glands (ducts and stroma);
- pigmentation of the areola and genital area;
- feminization (female type of development of secondary sexual characteristics);
- growth of epiphyses of tubular bones;
- promotes rejection of the endometrioid layer of the uterus due to which regulation occurs;
- activates blood clotting factors;
- helps increase the concentration of thyroxine (thyroid hormone), copper, iron;
- has an antiatherosclerotic effect;
- reduces cholesterol concentration.
Functions of estrogen in a woman’s body
With a lack of estrogen, pathological conditions develop in which pregnancy is unlikely or impossible. Divigel is often prescribed for IVF to correct and normalize hormonal levels.
The form of Divigel is a gel-like product applied to the skin. After the evaporation of the alcohol component of the gel, the molecules of synthetic estradiol penetrate deep into the subcutaneous layer and enter the vascular bed. Part of the active substance accumulates in the fatty layer, from here it enters the blood. Due to the fact that Divigel is used as a local drug, and not systemic (in the form of an injection or tablet), it does not have a toxic effect on the liver.
Contraindications to the use of the drug Divigel
Diagnosed, suspected or past breast cancer; diagnosed or suspected estrogen-dependent tumors (for example, endometrial cancer); vaginal bleeding of unknown etiology; untreated endometrial hyperplasia; thrombosis and thromboembolism (deep vein thrombosis, pulmonary embolism, myocardial infarction) within the last 2 years, a history of repeated thromboembolism; acute or chronic liver diseases (including a history) with changes in liver function tests; hypersensitivity to the components of the drug; During pregnancy and breastfeeding; porphyria.
Restrictions on use
It is not recommended to use Divigel in the following cases:
- volumetric processes of hormonally dependent genesis of any localization, especially in the reproductive organs and mammary glands;
- intolerance to gel components;
- blood discharge from the vagina of unknown etiology;
- high risk of blood clots;
- IHD, angina pectoris;
- previous myocardial infarction;
- history of stroke;
- severe liver and kidney failure;
- bronchial asthma;
- endometriosis;
- fibroid nodes in the uterus;
- pregnancy;
- lactation;
- for contraception.
Some of these contraindications are relative, so the doctor assesses the risks when using the drug and decides on its purpose and dose.
Divigel is prescribed taking into account the fact that it affects the effectiveness of hypotensive drugs, hypoglycemic drugs, and anticoagulants. The doctor correlates the use of the gel and medications used for diabetes, hypertension, and increased thrombus formation. Divigel is used only in consultation with the attending physician, who can professionally assess the clinical picture and the presence of concomitant diseases, analyze the situation, identify clear indications for the use of the drug, and select the appropriate dose of the drug for a particular patient as part of hormonal stimulation during IVF.
Indications
There are two main indications for using Divigel:
- Insufficient thickness of the endometrium. With IVF, an embryo is implanted into the uterus, which must attach securely to the endometrium, only then will pregnancy occur. The uterine layer should have a thickness of 7 millimeters or more; if it is less, the embryo will not be able to implant and it will end in a miscarriage. Divigel is prescribed for endometrial thickness of 5 millimeters or less.
- Deficiency of endogenous estradiol (that is, the one produced by the woman’s body).
In addition to artificial insemination programs, Divigel is used in postmenopausal women to prevent osteoporosis.
Endometrial growth in the natural cycle and with HRT
Interactions of the drug Divigel
Estrogens reduce the effectiveness of antihypertensive, antidiabetic agents and anticoagulants. Barbiturates, carbamazepine, rifampicin, griseofulvin and other activators of microsomal liver enzymes reduce the level of estradiol in the blood plasma. Ritonavir and nelfinavir, when used simultaneously with estrogens, may have an inducing effect. Preparations of St. John's wort can enhance the metabolism of estrogens and progestogens. Due to the lack of the effect of primary passage through the liver when using transdermal agents, the effect of liver enzyme inducers on metabolism is less pronounced.
Pharmacological properties of the drug Divigel
An alcohol-based gel containing estradiol (estra-1,3,5(10)-triene-3,17β-diol) is a synthetic analogue of human endogenous estradiol with similar biological effects. The action of Divigel is similar to the action of estrogens when administered orally: it compensates for estrogen deficiency, reducing the severity of disorders caused by menopause and oophorectomy. With sequential use of Divigel and progestogen, 80–90% of women experience regular menstrual-like bleeding with an average duration of 5–6 days, which usually begins within 1–7 days after the last dose of progestogen. Breakthrough bleeding and/or light spotting occurs during treatment in approximately 4–5% of women. Amenorrhea in the first year of treatment is observed in 3–5% of women. Transdermal use of estradiol in combination with medroxyprogesterone acetate helps reduce total cholesterol levels without changing the cholesterol/HDL ratio. The effectiveness of Divigel in correcting decreased bone density in the postmenopausal period is the same as with the use of oral estrogen drugs. When the gel is applied to the skin, the alcohol evaporates and estradiol is quickly adsorbed, entering the systemic bloodstream. Applying Divigel to a skin surface area of 200 or 400 cm2 (approximately equivalent to the area of one or two palms) does not affect the amount of estradiol absorbed, however, if Divigel is applied to a larger surface of the skin, the degree of absorption may change. A certain amount of estradiol accumulates in the subcutaneous fatty tissue, from where it is gradually released into the blood. Transdermal use avoids first-pass metabolism of the drug during its initial passage through the liver; for this reason, fluctuations in the concentration of estrogen in the blood plasma when using Divigel are significantly less pronounced than when taking estrogens orally. The maximum plasma concentration with transdermal use of estradiol at a dose of 1 mg is approximately 157 pmol/l, the average concentration in the interdose interval is 112 pmol/l, the minimum concentration is 82 pmol/l. The relative bioavailability of estradiol when used in the form of Divigel is 82% compared to an equivalent dose of estradiol valerate when administered orally.
Side effects
Divigel is well tolerated by patients in most cases.
But since the product contains an active hormonal element, the following adverse reactions may occasionally occur:
- tissue swelling (minor);
- headache or migraine;
- irritability, episodic psycho-emotional instability;
- increased blood pressure;
- increased heart rate;
- decreased libido;
- vaginal discharge of an atypical nature;
- weight gain;
- loss of appetite;
- dyspeptic disorders;
- hives or other skin rashes;
- liver dysfunction;
- cholestasis (decreased bile secretion or cessation of bile secretion).
These problems are usually not pronounced and are eliminated by adjusting the dose of Divigel by the attending physician or discontinuing the drug.
Special instructions for the use of the drug Divigel
Before starting or resuming hormone replacement therapy, it is necessary to conduct a complete medical examination of the patient (including examination of the pelvic organs and mammary glands). During treatment, periodic control examinations should be carried out, the scope of which (including mammography) is determined individually. Divigel should not be applied to the skin of the chest (especially the mammary glands), face, perineum, or damaged skin. Avoid getting the gel into your eyes. After applying the drug, wash your hands thoroughly. If the patient missed the time for applying the gel, it can be used only in the first 12 hours after the miss; if the gel was not applied at this time, the drug should be skipped and the next dose should be applied as scheduled. It must be remembered that during such omissions the patient may experience bleeding. Patients with endometriosis, endometrial hyperplasia, diseases of the cardiovascular system, cerebrovascular accidents, a history of thromboembolism, hypercoagulability phenomena, hypertension (arterial hypertension), a family history of breast cancer, impaired liver or kidney function, require careful monitoring during estrogen treatment. porphyria, uterine leiomyoma, epilepsy, asthma, diabetes mellitus, otosclerosis and multiple sclerosis, cholelithiasis, systemic lupus erythematosus. The drug should be discontinued immediately if liver dysfunction develops (including jaundice), a marked increase in blood pressure, attacks of migraine-like headaches, or pregnancy.
