Postmenopausal Tibolone Therapy: Biologic Principles and Applied Clinical Practice

Morris Notelovitz, MD, PhD, MB, BCh, FACOG, FRCOG

Disclosures
In This Article

Hormonal Biology

The pathways of estrogen biosynthesis and metabolism[6,7,8] are summarized in Figure 1. The primary source of the substrate for estrogen is the adrenal gland; ovarian androgens also serve as precursors but play a more minimal role. The steps in the bioconversion of androgens to estrogen are catalyzed by specific enzymes (3beta-hydroxysteroid dehydrogenase/delta isomerase; sulfatase and sulfotransferase; 17beta-hydroxysteroid dehydrogenase type 1,3 and type 2,4; or aromatase), each of which is controlled by a specific gene (cytochrome CYP17; CYP19). Aromatization of testosterone to estradiol is the main bioconversion pathway and takes place in extragonadal tissues, muscle, adipose tissue, breast, bone, brain and vascular endothelium and smooth muscle.[7,8] In addition, testosterone acts directly in peripheral tissues (eg, bone, brain) or by conversion via 5 alpha-reductase activity to the most biologically potent androgen - dihydrotestosterone. Aromatization of androgen to estrogen increases with aging.[7,8] Estrogen sulfate (the primary estrogen-derived pro-hormone) is converted to estrone via tissue sulfatase; estrone is then reversibly oxidized by 17beta dehydrogenase type 1 to estradiol. The net result is the postmenopausal change in dominance of the two estrogens with a reduction of the E2 to E1 ratio to less than 1. There is an overall decrease in the total amount of estrogen synthesized, the degree of which varies among individuals. The expression of the steroid-converting enzymes differs in and between the tissues of menopausal women, resulting in individualized tissue-selective metabolism.

Pathways and enzymes in estrogen, progesterone, and testosterone biosynthesis, metabolism and steroid receptor activity.

Both estradiol and estrone are metabolized to the biologically weaker estrogen, estriol, and to a number of other metabolites involving A-ring metabolic pathways (2 hydroxyestrone and its methylated form 2-methoxyestrone) or D-ring metabolism (16 alpha-hydroxyestrone). These pathways are also genetically controlled (CYP 1A1; CYP 1B1; COMT). The significance of these metabolites is their linkage to either anticarcinogenic (A-ring) or potential carcinogenic (D-ring) activity. Included in the latter category are the 4-hydroxyestrogens (Figure 1).[9]

Estrogens and androgens induce their biologic effects via binding to their respective estrogen (ER) and androgen (AR) tissue receptors.[7,10,11] These receptors are widely distributed throughout the body and are found in organs far removed from the reproductive tract. There are 2 ERs; the alpha receptor is dominant in tissues such as the breast, endometrium, ovarian stroma and vagina; and the beta receptor is concentrated in target tissues such as the brain, bone, endothelial cells of the coronary arteries, intestines, and kidneys. The distribution of these receptors within a given individual is organ- and tissue-specific, and may be homogenous (alpha/alpha-dimers or beta/beta-dimers)or heterogenous (alpha/beta-dimers).[7,10] The alpha/beta distribution determines the individual's response both to her endogenous and exogenous hormonal milieu. The beta receptor - most notably in the breast - modulates and downregulates the activity of the alpha receptor. Testosterone upregulates breast ERbeta.[12] The binding of the estrogen ligand to the estrogen response element is controlled by a complex interplay of estrogen co-activators and co-repressors. Estrogen-induced transcription occurs via the classic genomic nuclear receptor, a nongenomic membrane receptor and even an estrogen-independent mechanism.[7] Mutations of the receptor can enhance or reduce their sensitivity to ligand binding and transcription.

There are at least 2 isoforms of the progesterone receptor (PR), subtypes A (PRA) and B (PRB).[13] PRA is a dominant negative regulator for the classic nuclear receptors: PRB; ER; and AR and the glucocorticoid (GR) and mineralocorticoid receptors (MR).[13] Progesterone receptors have been identified in human breast tumors and the endometrium.

The liver impacts on the bioactivity of estrogen and androgen in 3 main respects: metabolism of estrone and estradiol, enterohepatic metabolism of estradiol to estrone,[7,10] and the synthesis of sex hormone-binding globulin (SHBG).[14] Both estrogen and testosterone are avidly bound to SHBG. The degree of binding determines the bioavailability of both estradiol and testosterone. An increase of SHBG reduces the tissue bioavailability of both estradiol and testosterone.[15]

The variability of endogenous estrogen and androgen biosynthesis partly explains the difference in prevalence and severity of menopausal symptoms and menopause-related conditions. Knowledge of endogenous steroid synthesis and metabolism provides an important basis for rationalizing the use of ET/HT receptor and/or steroid-converting enzyme-related drugs. Significant estrogen metabolism occurs in various target tissues and results in local concentrations of steroid far in excess of that measurable in the systemic circulation.[16] Thus, circulating levels of estrogen and androgen do not necessarily reflect the tissue concentrations of bioactive hormone.

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