Estragyn

CLINICAL PHARMACOLOGY

Mechanism Of Action

Estrogen drug products act by regulating the transcription of a limited number of genes. They may act directly at the cell's surface via a non “estrogen receptor” mechanism or directly with the estrogen receptor inside the cell. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein which is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or hormone-response elements, which enhance the transcription of adjacent genes and in turn lead to the observed effects. Estrogen receptors have been identified in the wall of blood vessels, in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women.

Pharmacodynamics

Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. They promote growth and development of the vagina, uterus, and fallopian tubes, and enlargement of the breasts. Indirectly, they contribute 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 the pubertal growth spurt and its termination, growth of axillary and pubic hair, and pigmentation of the nipples and genitals. Along with other hormones such as progesterone, estrogens are intricately involved in the process of enstruation. Estrogens also affect the release of pituitary gonadotropins.

A depletion of endogenous estrogens occurs postmenopausally as a result of a decline in ovarian function, and may cause symptomatic vulvovaginal atrophy.

Pharmacokinetics

Absorption

Estrone is water soluble and can be readily absorbed into the blood stream through skin and mucous membranes.

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are distributed in the body and generally found in higher concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Metabolism

Absorbed hormone is metabolized by the liver much the same as endogenous hormone. Complex metabolic processes create a dynamic equilibrium of inter conversion between estrone and estradiol and between esterified and non esterified forms.

Estrogen administered intravaginally is not subject to true “first-pass” metabolism, but will undergo hepatic uptake, metabolism, and enterohepatic recycling. Metabolism and inactivation occur primarily in the liver. Some estrogens are excreted into the bile; but, they are re-absorbed from the intestine and returned to the liver through the portal venous system. Water-soluble estrogen conjugates are strongly acidic and are ionized in body fluids, which favour excretion through the kidneys since tubular re-absorption is minimal.

Excretion

A portion of the estrogen is excreted into the bile to be reabsorbed via the intestine and back to the liver. During the course of enterohepatic recirculation, estrogens are desulfated and resulfated, undergo degradation to less active estrogens such as estriol, are oxidized to nonestrogenic substances which interact with catecholamine metabolism and are conjugated with glucuronic acids to be excreted in the urine.

Special Populations And Conditions

No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

Estrogen Pharmacology

There are 3 main estrogens found in the human body they being 17β-estradiol, estrone and estriol. Estradiol the most potent is produced by the ovarian follicle during child bearing years. However at menopause most estrogen is derived from the conversion of androstenedione to estrone by peripheral tissues. In the case for estrone in a vaginal cream the estrogen is present to bind to the receptors of estrogen responsive tissue that line the vagina.

Although the amount of estrone available per treatment is low, the concomitant use of a progestin is a necessary precaution to protect against endometrial hyperplasia in women with intact uteri.

Pivotal Clinical Trials

Efficacy and Safety Studies

There have been no pivotal clinical trials specific to the use of Estragyn Vaginal Cream. Moreover there is not an abundance of published studies on the use of intra vaginal estrogen therapy. The estrogens currently available are of a diverse range which includes conjugated estrogens, 17 beta-estradiol, and estrone. Also they vary in the delivery systems used: vaginal creams versus vaginal tablets versus vaginal rings. However common characteristic of these low dose vaginal applied hormones is that they effectively alleviate the symptoms of vaginal atrophy. Early investigation shows cytological and subjective improvement after low dose intra vaginal treatment over relatively short periods of time.10,11,12 Again this assessment is reflected in the Cochrane Collaboration: Local estrogen for vaginal atrophy in postmenopausal women (Review).13 On a subjective evaluation there were differences noted between groups receiving estrogens as compared to a non-estrogenic moisturizer. However there were no significant differences between estrogen receiving groups for assessment of atrophy, pallor, petechaie, friability, and dryness. In cytological assessment there were no significant differences between groups for karyopknotic index, maturation value and vaginal health index. In terms of safety there were no significant differences between groups for outcomes of hyperplasia, proliferation of the endometrium or endometrial thickness. As a cautionary statement and also pointed out by the authors any interpretation has to consider that the review was based on combined results of many separate trials with: trial variation, small trial numbers and significant variance in results. Also these studies do not look at long term effects of treatment and therefore the full term treatment should not be extended without consideration of closer monitoring.13

It is also well known and demonstrated that intra-vaginal applied hormones are absorbed systemically. In light of the findings of the WHO on HRT a concern was raised on the estrogenic link to breast cancer. However that study did not include vaginal applications of low dose estrogens. Published data by Dew J.E. et al did not appear to associate topical vaginal estrogen therapy with an increased risk of breast cancer however that study was too small in numbers to be conclusive14. Kendall et al in the Annals of Oncology January 2006 was able to demonstrate raised systemic estradiol levels in patients having taken low dose vaginal tablets. These patients were in a high risk category and taking an adjuvant aromatase inhibitors and concludes that this treatment is contraindicated in this group of patients15. Until greater assurance is available, persons at higher risk should not be candidates for intra-vaginal estrogen therapy.

Detailed Pharmacology

See Actions and Clinical Pharmacology section under Part I.

Toxicology

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

REFERENCES

10. Cardozo L, Bachmann G, McClish D, Fonda D, Birgerson L. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol. 1998;92(4 pt 2): 722-727

11. Handa VL, Bachus KE, Johnston WW, Robboy SJ, Hannond CB. Vaginal administration of low-dose conjugated estrogens: systemic absorption and effects on the endometrium. Obstet Gynecol.1994;84(2):215-218

12. Rioux JE, Devlin C, Gelfand MM, Steinberg WM, Hepburn DS. 17 beta-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. Menopause. 2000;7(3):156-161

13. Suckling J, Lethaby A, Kennedy R. Local estrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev 2003; CD001500.

14. Dew JE, Wren BG, Eden JA. A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer. Climacteric 2003;6:45-52

15. Kendall A, Dowsett M, Folkerd E, Smith I. Caution: Vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Annals of Oncology 2006;17(4):584-587

Last reviewed on RxList: 3/31/2014
This monograph has been modified to include the generic and brand name in many instances.

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