Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Sex hormones and modulators of the genital system - natural and semisynthetic oestrogens, plain.
ATC Code: G03CA03.
As oestrogens promote the growth of endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen greatly reduces the oestrogen- induced risk of endometrial hyperplasia in non-hysterectomised women.
As the major oestrogen secreted by the human ovary, oestradiol is crucial to the development and maintenance of the female reproductive system and secondary sex characteristics, it promotes growth and development of the vagina, uterus and fallopian tubes, and enlargement of the breasts. Indirectly it contributes to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for pubertal growth spurt and its termination, growth of axillary and pubic hair and pigmentation of the nipples and genitals.
The onset of menopause results from a decline in the secretion of oestradiol and other oestrogens by the ovary resulting initially in the cessation of menstruation, followed by menopausal symptoms such as vasomotor symptoms (hot flushes and sweating), muscle cramps, myalgias, arthralgias, anxiety, atrophic vaginitis and kraurosis vulvae. Oestrogens are also an important factor in preventing bone loss and after the menopause women lose bone mineral content at an average rate of 15-20% in a ten year period.


Clinical trial information
• Relief   of oestrogen deficiency symptoms and bleeding patterns Relief of menopausal symptoms was achieved during the first few weeks of treatment. The rate of regular withdrawal bleeding or amenorrhoea depends on the individual posology and may vary on the individual patient.
• Prevention    of osteoporosis
- Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass.
- The effect of oestrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a similar rate to that in untreated women.
- Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestogen – given to predominantly healthy women- reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for this is limited.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Pharmacokinetic studies indicate that, when applied topically to a large area of skin in a volatile solvent, approximately 10% of the oestradiol is percutaneously absorbed into the vascular system, regardless of the age of the patient.
Distribution

Daily application of 2.5 g or 5 g Oestrogel over a surface area of 400-750 cm2 results in a gradual increase in oestrogen blood levels to steady state after approximately 3-5 days and provides circulating levels of both oestradiol and estrone equivalent in absolute concentrations and in their respective ratio to those obtained during the early-mid follicular phase of the menstrual cycle.
Oestrogel was administered to 17 postmenopausal women once daily on the posterior surface of one arm from wrist to shoulder for 14 consecutive days.
Maximum serum concentrations (Cmax) of oestradiol and estrone on Day 12 were 117 pg/ml and 128 pg/ml, respectively.
The time-averaged serum oestradiol and estrone concentrations (Caverage) over the 24hour dose interval after administration of 2.5 g of Oestrogel on Day 12 were 76.8 pg/ml and 95.7 pg/ml, respectively.
Biotransformation
Metabolism of oestradiol takes place mainly in the liver under oestriol, estrone and their conjugated metabolites (glucuronides, sulphates). These metabolites also undergo enterohepatic recirculation.
When treatment is stopped, oestradiol and urinary conjugated oestradiol concentrations return to baseline in about 76 hours.
Elimination
Oestriol is the major urinary oestradiol metabolite. However, glucuronide and sulphate metabolites of oestradiol and oestrone are also found in urine and bile. Metabolites excreted in bile undergo enterohepatic recirculation or are excreted in the faeces.