Focus on Estradiol Valerate/Levonorgestrel

Siegfried Golbs(1) DVM, PhD, Rumen Nikolov(2) MD, PhD, Thomas Gräser (1) MD, PhD, Thomas Zimmermann(1) MD, PhD

(1)Jenapharm GmbH & Co. KG, Jena, Germany (2)Chemical Pharmaceutical Research Institute, Sofia, Bulgaria

Introduction

The benefits of hormone replacement therapy (HRT) include alleviation of vasomotor menopausal complaints such as hot flushes and night sweats, improvement of mood, psychological well-being and quality of life, and management of the symptoms resulting from postmenopausal urogenital atrophy. Long-term benefits include reduced risk of osteoporosis, cardiovascular disease, and Alzheimer's disease. The daily dose of 2 mg estradiol valerate (EV) assures sufficient estrogen replacement, but unopposed estrogen administration may cause hyperplasia of the endometrium and endometrial cancer (Grady et al., 1995; Persson et al., 1996). The role of the progestogens in the combined HRT in women with an intact uterus is to prevent the development of estrogen-induced endomentrial hyperplasia, and thus to decrease the risk of endometrial cancer (Grady et al., 1995; La Veccia et al., 2001). A selection of a suitable progestogen is very important for the development of a combined HRT drug (Goeretzlehner, 2001). Due to its strong progestational effect on the endometrium, and its antiestrogenic effect, levonorgestrel is very effective in suppression of the estrogen-induced endometrial proliferation (Rozenbaum, 1996; Stanczyk, 1996; Goeretzlehner, 2001).

Estradiol valerate/levonogrestrel (EV/LNG, KlimonormÒ, Jenapharm GmbH & Co. KG) is a sequential oral estrogen-progestogen HRT containing 2 mg estradiol valerate (EV) during the first phase (9 days), and 2 mg EV plus 0.150 mg levonorgestrel (LNG) in the second phase (12 days). The 21 days of tablet intake are followed by a 7-day medication-free period.

Pharmacodynamic profile

Estradiol valerate (EV) represents the natural estrogen estradiol esterified at position 3 with valeric acid, which after ingestion is rapidly hydrolyzed in the intestines in estradiol.

The effects of EV are comparable to that of the same molar dose of micronized estradiol. They are dose and time dependent:

EV stimulates the proliferation of vaginal, urethral, and bladder epithelia.
EV stimulates the proliferation of skin epidermal cells and the synthesis of collagen and hyaluronic acid.
EV improves effectively the climacteric complaints - at a dose of 2 mg 60 - 70 % of the patients experience satisfactory relief.
EV improves sleep quality and reduces wakening episodes associated with hot flushes.
EV improves urogenital complaints associated with atrophic changes.
At a dose of 2 mg daily, EV is effective in the prevention of osteoporosis in postmenopausal women by inhibition of osteoclast function and improvement of calcium retention and absorption.
EV increases the serum levels of triglycerides and HDL cholesterol and decreases those of total cholesterol, LDL cholesterol and lipoprotein(a).

Thus EV is effective for treatment of symptoms associated with estrogen deficiency. At doses between 1 mg and 4 mg, EV is used in many preparations for treatment of peri- and postmenopausal complaints.

Levonorgestrel (LNG), the active dextro-rotatory isomer of norgestrel, is one of the most widely used synthetic progestogens.

LNG:

Binds with high affinity to the progesterone receptor, and shows a potent progestational action.

Binds with high affinity to the androgen receptors, but shows a weak androgenic effect in humans.

Does not interact with the estrogen receptors, and does not show estrogen agonist effect, but has a strong antiestrogenic action.

LNG is used nowadays as the progestogen component of several oral contraceptives and hormone replacement products. Due to its profound progestational action on the endometrium, LNG is effective for transformation of estrogen-induced proliferation of the endometrium leading to withdrawal bleeding.

Pharmacokinetic profile

The pharmacokinetic parameters of EV/LNG are summarized by Golbs et al. (2001). After single oral administration of 2 mg EV (first phase), Cmax of free estradiol is 38.8 pg/ml, tmax - 7.8 h, and t1/2b - 15.9 h. After single oral administration of 2 mg EV plus 0.15 mg LNG (second phase) Cmax of free estradiol is 52.4 pg/ml, tmax - 11.9 h, and t1/2b - 16.1 h, Cmax of LNG is 6.2 ng/ml, tmax - 1.0 h, and t1/2b - 31.7 h. The higher values of Cmax after addition of LNG are explained by LNG-induced decrease of estradiol metabolism. The half-life of LNG is increased by addition of estradiol from 19 to 31.7 h.

Alleviation of climacteric symptoms

Postmenopausal estrogen deficiency results in the classical menopausal complaints such as hot flushes, sweating, anxiety and depression.

The effect of EV/LNG on the alleviation of the climacteric symptoms is studied:

In the condition of a multicenter, randomized, double-blind study on 210 postmenopausal women using two sequential regimens (Gräser et al., 1997). The high-LNG group is treated with 2 mg EV (days 1-21) sequentially combined with 0.25 mg LNG (days 12-21), and the low-LNG group - with 2 mg EV, days (1-21) sequentially combined with 0.15 mg LNG (days 10-21). Both regimens are similarly effective in alleviation of the climacteric complaints. The mean total score of the Kupperman index decreases considerably after 3 months of therapy (from 19.6 to 5.5), and a further decrease to 3.6 is observed after 6 months treatment.
In a multicenter postmarketing study on 78 peri- and postmenopausal women Rudolph et al. (2000) establish a marked improvement of the Kupperman index (a decrease from 30.5 to 16.5 scores, p<0.05) after 2 months use of EV/LNG.
In an extensive postmarketing study on 10,459 women the efficacy of EV/LNG in the treatment of postmenopausal symptoms is assessed using the objective parameter Kupperman index, and the subjective parameter impressions of the users. The Kupperman index decreases by more than 55% in 88.4% of the patients after 3 months of treatment. The subjective impressions of the users show that 50% of them are free of complaints already after 4 weeks. At 12 weeks about 90% have no complaints (Zimmermann et al., 2001).
In a study on 123 postmenopausal women treated with EV/LNG Burdová et al. (2001) find a statistically significant (p<0.0001) decrease of the Kupperman index from the initial score of 25 to 7.6 after 6 months and to 1.6 after 9 months.
Effect on psychic state

In a multicenter, prospective, open-label postmarketing surveillance trial Rudolph et al. (2000) study the changes in psychic and somatic well-being, self-esteem and cognitive capabilities of 78 peri- and postmenopausal women after 2-months treatment with EV/LNG. EV/LNG causes a distinct improvement in subjective psychosomatic well-being and a slight increase of the concentration and cognitive capabilities of the women.

Effect on postmenopausal osteoporosis

The effect of EV/LNG on postmenopausal osteoporosis is investigated in:

An open trial on 33 peri- and postmenopausal women with an average age of 53.7 years. Cortical, subcortical and spongious bone mass is examined on the radius using peripheral quantitative computer tomography. The cortical bone mass increases by an average of 4% after 12 months of treatment. In the majority (n=20) of patients, EV/LNG increases the development of spongious bone mass (on average by 7%). The increase is most pronounced in the 60-74 year age range (Golbs, 1998).
An open study on 43 postmenopausal women (average age 51.7 years) with lumbar osteoporosis. A densitometric analysis of the bone density in the lumbar region (L1-L4) is performed. The results show an average increase of the bone mass by 4.9% after 12 months treatment with EV/LNG. Bone mass increases in 68% of the patients, and does not change in the rest of patients (Radowicki, 1998).
A clinical study on 74 nonmenopausal women with surgically-induced menopause who are treated with EV/LNG for a period of one to two years. Therapy with EV/LNG significantly improves the reduced by the surgical menopause bone mineral density, T-score, and Z-score. EV/LNG reverses also the evoked by the surgically-induced menopause increase of alkaline phosphatase, and significantly lowers the increased excretion of Ca2+ by urine (Živný et al., 2001).

Effect on urogenital atrophy

EV/DNG improves considerably the urogenital complaints. Dancsó et al. (1998) investigates 25 postmenopausal women with urogenital complaints who are treated for 12 months with EV/LNG. The efficacy of the treatment is evaluated by monitoring of the clinical complaints, vaginal pH, and vaginal cytology. During the treatment the subjective urogenital complaints (vaginal discomfort, dysuria, urinary frequency) are reduced already after 3 months and considerably improve after one year of treatment. The improved objective signs are thickening of the atrophic epithelium, decrease of the vaginal pH, reduction of colpitis, and improvement of the cell morphology of the vaginal cells.

Lipid metabolism

Gräser et al. (1997) investigate the effect of EV/LNG on lipid metabolism after administration of EV/LNG for six cycles. EV/LNG causes:

A significant (p<0.05) decrease of the plasma concentrations of triglycerides, high-density lipoprotein (HDL) cholesterol, lipoprotein(a) and apolipoprotein A1.
A slight insignificant increase of LDL-cholesterol.
A slight increase (8.4%, p<0.05) of the serum concentration of total cholesterol.

Burdová et al. (2001) study the effect of EV/LNG on lipid metabolism in 123 menopausal women (mean age 51 years). The duration of therapy is 36 months. EV/LNG causes:

A significant decrease of total cholesterol and LDL-cholesterol.
A significant increase of the HDL-cholesterol levels. The changes are most pronounced after 3 years of treatment.
A steadily decrease of triglycerides during the therapy.

The difference of the changes of the lipid metabolism in both studies are due most probably to the difference in the treatment period - 6 months in that of Gräser et al. (1997) and 3 years in that of Burdová et al. (2001).

Modification of the estrogen effects by co-administration of LNG

An important problem with the use of opposed HRT regimen is that the progestogen component might reverse the beneficial effects of estrogen on the cardiovascular system. The antioxidative effect of estrogen is well established. 17b-estradiol also inhibits the oxidation of LDL ex vivo (Keaney et al., 1994). Sack et al. (1994) first report that 17b-estradiol prolongs the lag phase of LDL oxidation in postmenopausal women.

Schröder at al. (1996) investigate the influence of LNG on the inhibition of the LDL lipoprotein oxidation by 17b-estradiol or 17b-EV in vitro and ex vivo. In vitro 17b-estradiol increases dose-dependently the lag time of the LDL-oxidation. Addition of different doses of LNG does not modify the antioxidative action of estrogen. In rabbits LNG does not antagonize the estradiol-induced effect. In postmenopausal women the administration of LNG does not diminish the antioxidative action of 17b-EV. Thus the antioxidative effect of estradiol and EV is maintained in the presence of LNG.

Effects on cycle and bleeding pattern

The strong progestational effect of LNG on the endometrium results in a stabilization of the menstrual cycle. In most of the women the cycle length is stabilized at about 3-4 days. Therapy with EV/LNG results in a weaker and pain-free menstruation and cycles with regular withdrawal bleeding are restored in more than 90% of the women (Gräser et al., 1997; Burdova et al., 2001; Radowicki, 1998; Georgiev, 2001). In the study of Georgiev (2001) on 46 women the duration of bleeding decreases significantly from 5.1 days at the start to 4.1 days after 3 months, and to 3,8 days after 6 months treatment.

Endometrial safety

The thickness of the endometrium measured sonographically does not change significantly during three years therapy with EV/LNG (Burdova et al., 2001). A slight insignificant reduction of the endometrial thickness is observed in the study of Georgiev (2001).

Clinical safety

The tolerability of EV/LNG is very good as shown in the clinical and postmarketing studies. There are no clinically significant changes in body weight, blood pressure, hematological tests, and other laboratory parameters reported during treatment with EV/LNG (Gräser et al., 1997; Burdová et al., 2001; Zimmermann et al., 2001; Živný et al., 2001).

Epidemiological studies have shown that postmenopausal HRT may increase the risk of venous thromboembolism (Daly et al., 1996; Grodstein et al., 1996; Gutthann et al., 1997). The studies showed about two-fold increased risk which is highest in the beginning of the treatment and is restricted for the first year of use. Due to the increased risk, LNG-containing HRT should be applied cautiously in women at risk of developing deep venous thrombosis or pulmonary embolism, and is contraindicated in patients with active thromboembolic disease.

Conclusion

The clinical effectiveness of EV/LNG is demonstrated by an alleviation of the classical vasomotor menopausal complaints, improvement of subjective psychosomatic well-being and cognitive capabilities of the women, prevention of postmenopausal osteoporosis, counteraction of the symptoms and signs of urogenital atrophy, and favorable effect on lipid metabolism. Therapy with EV/LNG results in stabilization of the cycle length to about 3-4 days. Cycles with regular withdrawal bleeding are restored in most of the women. The thickness of the endometrium measured sonographically does not change significantly after 3 years of KlimonormÒ intake. The antioxidative action of estradiol is not eliminated in the presence of LNG. EV/LNG is safe and well tolerated by most of the women.

References

Burdová, K., Kancheva, R., Hill, M. (2001) Results of a long-term study in hormone replacement therapy with Klimonorm®. Drugs Today 37 (Suppl. C), 23-9.

Daly, E., Vessey, M.P., Hawkings, M. et al. (1996) Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 348, 977-80.

Dancsó, J., Kanizsai, B., Konczwald, L. (1998) Effect of KlimonormÒ hormone replacement therapy on urogenital complaints. In: S. Golbs, Ed. Efficacy and Tolerability - HRT with KlimonormÒ. Jenapharm GmbH&Co.KG, Jena, Germany, pp. 62-8.

Georgiev, D.B. (2001) Endometrial safety during administration of the combined estrogen-progestogen hormone replacement drug Klimonorm® in perimenopausal women. Drugs Today 37 (Suppl. C), 31-5.

Goeretzlehner, G. (2001) The role of progestogens in hormone replacement. Drugs Today 37 (Suppl. C), 1-8.

Golbs, S. (1998) Pharmacology of KlimonormÒ. In: S. Golbs, Ed. Efficacy and Tolerability - HRT with KlimonormÒ. Jenapharm GmbH&Co.KG, Jena, Germany, pp. 27-35.

Golbs, S., Zimmermann, H., Nikolov, R. et al. (2001). The pharmacological and clinical profile of KlimonormÒ. Drugs Today 37 (Suppl. C), 9-18.

Grady, D., Gebretsadik, T., Kerlikowske, K., Ernster, V., Petitti, D. (1995) Hormonal replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 85, 304-13.

Gräser, T., Rößner, P., Schubert, K., Müller, A., Bönisch, U., Oettel, M. (1997) A comparative study of two levonorgestrel-containing hormone replacement therapy regimens on efficacy and tolerability variables. Maturitas 28, 169-79.

Grodstein, F., Stampfer, M.J., Goldhaber, S.Z. et al. (1996) Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 348, 983-7.

Gutthann, S.P., Rodrigues, L.A.B., Castellsague, J., Oliart, A.D. (1997) Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. Br Med J 314, 976-800.

Keaney, J.F.,Jr., Shwaery, G.T., Xu, A. et al. (1994) 17b-estradiol preserves endothelial vasodilator function and limits low-density lipoprotein oxidation in hypercholesterolemic swine. Circulation 89, 2251-9.

La Veccia, C., Brinton, L.A., McTiernan, A. (2001) Menopause, hormone replacement therapy and cancer. Maturitas 39, 97-115.

Persson, I., Yuen, J., Bergkvist, L., Schaerer, C. (1996). Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy - long-term follow-up of a Swedish cohort. Int J Cancer 67, 327-32.

Radowicki, S. (1998) KlimonormÒ and hormone replacement therapy. In: S. Golbs, Ed. Efficacy and Tolerability - HRT with KlimonormÒ. Jenapharm GmbH&Co.KG, Jena, Germany, pp. 40-50.

Rozenbaum, H. (1996) Progestins and endometrial safety: The French point of view. Drugs Today 32 (Suppl. H), 15-23.

Rudolph, I., Zimmermann, T., Kaminski, K. et al. (2000) Changes in psychic and somatic well-being and cognitive capabilities of peri- and postmenopausal women after the use of a hormone replacement drug containing estradiol valerate and levonorgestrel. Methods Find Exp Clin Pharmacol 22, 51-6.

Sack, M.N., Rader, D.J., Cannon, R.O. (1994) III. Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women. Lancet 343, 269-70.

Schröder, J., Dören, M., Schneider, B., Oettel, M. (1996) Are the antioxidative effects of 17b-estradiol modified by concomitant administration of a progestin? Maturitas 25, 133-9.

Stanczyk, F.Z. (1996) Introduction: Structure-function relationships, metabolism, pharmacokinetics and potency of progestins. Drugs Today 32 (Suppl. H), 1-14.

Zimmermann, T., Wisser, K.-H., Dietrich, H., Domhardt, R., Chemnitius, K.-H. (2001) Post-marketing surveillance studies of KlimonormÒ in Central and Eastern Europe. Drugs Today 37 (Suppl. C), 19-22.

Živný, J., Jenícek, J., Fait, T., Kocian, J., Vinglerová, H. (2001) Changes in bone density and bone metabolism in women with surgically-induced menopause treated with a hormone replacement drug containing estradiol valerate and levonogestrel. Drugs Today 37 (Suppl. C), 37-44.

Correspondence:

Siegfried Golbs DVM, PhD

Department of Medical Affairs, Jenapharm GmbH & Co. KG, Otto-Schott St. 15, 07745 Jena, Germany.

Tel.: +49-3641-646 527; Fax: +49-3641-646104

Email: Siegfried.Golbs@Jenapharm.de

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