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

•    Estradiol/estradiol valerate:

Progynova contains estradiol valerate, (the valeric-acid ester of the endogenous female oestrogen, estradiol.

The active ingredient estradiol valerate, a prodrug of the synthetic 17ß-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy.

Ovulation is not inhibited during the use of Progynova, and the endogenous production of hormones is hardly affected.

Clinical trial information

Relief of oestrogen-deficiency symptoms and bleeding patterns
-   During the climacteric, the reduction and finally loss of ovarian estradiol secretion can result in instability of thermoregulation, causing hot flushes associated with sleep disturbance and excessive sweating, and urogenital atrophy with symptoms of vaginal dryness, dyspareunia and urinary incontinence. Less specific but often mentioned as part of the climacteric syndrome are symptoms like anginal complaints, palpitations, irritability, nervousness, lack of energy and concentration abilities, forgetfulness, loss of libido and joint and muscle pain.
HRT alleviates many of these symptoms of estradiol deficiency in the menopausal woman.
-   Relief of menopausal symptoms was achieved during the first few weeks of treatment.
-   The addition of a progestogen to an oestrogen replacement regimen like Progynova for at least 10 days per cycle is recommended in women with an intact uterus. It reduces the risk of endometrial hyperplasia and the attendant risk of adenocarcinoma in these women. The addition of a progestogen to an oestrogen replacement regimen has not been shown to interfere with the efficacy of oestrogen for its approved indications.

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 rate similar 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 that is limited.

Observational studies and the WHI trial on conjugated equine oestrogens (CEE) plus medroxyprogesterone acetate (MPA) suggest a reduction of colon cancer morbidity in postmenopausal women taking HRT. In the WHI trial on CEE mono-therapy a risk reduction was not observed. It is unknown whether these findings also extend to other HRT products.
•   Progestogen:

As oestrogens promote the growth of the 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.

Pharmacokinetic Properties

5.2.   Pharmacokinetic Properties
Absorption
After oral administration estradiol valerate is quickly and completely absorbed.

Distribution
Already after 0.5 - 3 hours peak plasma levels of estradiol, the active drug substance, are measured. As a rule, after 6 - 8 hours a second maximum appears, possibly indicating an entero-hepatic circulation of estradiol.

In plasma, estradiol is mainly found in its protein-bound form. About 37% are bound to SHBG and 61% to albumin. Cumulation of estradiol after daily repetitive intake of Progynova does not need to be expected.

The absolute bioavailability of estradiol amounts to 3 - 5% of the oral dose of estradiol valerate.

Biotransformation
Esterases in plasma and the liver quickly decompose estradiol valerate into estradiol and valeric acid. Further decomposition of valeric acid through β-oxidation leads to C2-units and results in CO2 and water as end products. Estradiol itself undergoes several hydroxylating steps. Its metabolites as well as the unchanged substance are finally conjugated. Intermediate products of metabolism are estrone and estriol, which exhibit a weak oestrogenic activity of their own, although this activity is not so pronounced as with estradiol. The plasma concentration of conjugated estrone is about 25 to 30 fold higher than the concentration of unconjugated estrone. In a study using radioactive labelled estradiol valerate about 20% of radioactive substances in the plasma could be characterised as unconjugated steroids, 17% as glucuronized steroids and 33% as steroid sulphates. About 30% of all substances could not be extracted from the aqueous phase and, therefore, probably represent metabolites of high polarity.

Elimination
Estradiol and its metabolites are mainly excreted by the kidneys (relation of urine:faeces = 9:1). Within 5 days about 78 - 96% of the administered dose are excreted with an excretion half-life of about 27 hours.