Progynova Mechanism of Action

Pharmacology: Estradiol valerate, an estrogen, is a prodrug of the natural human 17β-estradiol.
Ovulation is not inhibited during the use of Progynova, and the endogenous production of hormones is hardly affected.
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 eg, anginal complaints, palpitations, irritability, nervousness, lack of energy and concentration abilities, forgetfulness, loss of libido, and joint and muscle pain. Hormone replacement therapy (HRT) alleviates many of these symptoms of estradiol deficiency in the menopausal woman.
HRT with an adequate estrogen dosage like in Progynova reduces bone resorption and retards or halts postmenopausal bone loss. When HRT is discontinued, bone mass declines at a rate comparable to that in the immediate postmenopausal period. There is no evidence that HRT restores bone mass to premenopausal levels. HRT also has a positive effect on skin collagen content and skin thickness and can retard the process of skin wrinkling.
In recent years, many published studies have suggested that there may be a cause-effect relationship between postmenopausal oral HRT and a decrease in cardiovascular disease in women. A causal relationship between HRT and reduction of cardiovascular disease in postmenopausal women has not yet been proven. Furthermore, the effect of added progestogens on this putative benefit is unknown.
Unfavorable effects on lipid and nonlipid cardiovascular risk factors may contribute to the increased incidence of cardiovascular disease seen in women in the postmenopause. HRT changes the lipid profile. It lowers total cholesterol and LDL-cholesterol and may increase HDL-cholesterol and triglyceride levels. The metabolic effects may be counteracted to some extent by the addition of a progestogen. In general, the metabolic effects of HRT are considered beneficial and contributing to the assumed risk reduction of cardiovascular disease in postmenopausal women.
The addition of a progestogen to an estrogen replacement regimen eg, 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 estrogen replacement regimen has not been shown to interfere with the efficacy of estrogen for its approved indications.
Pharmacokinetics: Absorption: Estradiol valerate is rapidly and completely absorbed. The steroid ester is cleaved into estradiol and valeric acid during absorption and the first liver passage. At the same time, estradiol undergoes extensive further metabolism eg, into estrone, estriol and estrone sulfate. Only about 3% of estradiol becomes bioavailable after oral administration of estradiol valerate. Food does not affect the bioavailability of estradiol.
Distribution: Maximum concentrations of estradiol in serum of approximately 15 pg/mL (or 30 g/mL) are generally expected between 4-9 hrs after tablet intake. Within 24 hrs after tablet intake, serum levels of estradiol are expected to decline to concentrations of about 8 pg/mL (or 15 pg/mL). Estradiol binds to albumin and the sex hormone-binding globulin (SHBG). The unbound fraction of estradiol in serum is about 1-1.5% and the SHBG-bound fraction is in the range of 30-40%.
The apparent volume of distribution of estradiol after single IV administration is about 1 L/kg.
Metabolism: After the ester cleavage of the exogenously administered estradiol valerate, the metabolism of the drug follows the biotransformation pathways of endogenous estradiol. Estradiol is mainly metabolized in the liver but also extrahepatically eg, in gut, kidney, skeletal muscles and target organs. These processes involve the formation of estrone, estriol, catecholestrogens and sulfate and glucuronide conjugates of these compounds, which are all distinctly less estrogenic or even non-estrogenic.
Elimination: The total serum clearance of estradiol following single IV administration, shows high variability in the range of 10-30 mL/min/kg. A certain proportion of estradiol metabolites are excreted in the bile and undergo a so-called enterohepatic circulation. Ultimately, estradiol metabolites are mainly excreted as sulfates and glucuronides with the urine.
Steady-State Conditions: In relation to the single dose, approximately 2 times higher serum levels of estradiol are expected after multiple administration. On average, the concentration of estradiol varies between 15 (or 30 pg/mL) (minimum levels) and 30 (or 60 pg/mL) (maximum levels). Estrone, as a less estrogenic metabolite, reaches about 8 times higher concentrations in serum, estrone sulfate reaches approximately 150 times higher concentrations. After stopping the treatment, pre-treatment levels of estradiol and estrone are reached within 2-3 days.
Toxicology: Preclinical Safety Data: Carcinogenicity: The results from toxicity studies with repeated administration including tumorigenicity studies are not suggestive of a particular risk related to use in humans. However, it has to be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.
Embryotoxicity/Teratogenicity: Reproduction toxicological investigations with estradiol valerate gave no indications of a teratogenic potential. As no nonphysiological estradiol plasma concentrations are produced by administration of estradiol valerate, Progynova does not present a risk to the fetus.
Mutagenicity: In vitro and in vivo studies with 17β-estradiol gave no indications of a mutagenic potential.