Estrogen Kinetics for Clinicians
John E. Buster
Table Of Contents
John E. Buster, MD
KINETICS OF ENDOGENOUS ESTROGENS
REGULATION OF ESTROGEN EXPRESSION
KINETICS OF EXOGENOUS ESTROGEN
Knowledge of estrogen kinetics is essential to clinicians providing gynecologic care. During the past decade, concepts involving estrogen kinetics have been key elements in the design of oral contraceptives, in the development of menopausal replacement therapy, in the tailoring of reproductive hormone support for transplanted embryos, and in hormone therapy of malignancies. In addition to affecting the female reproductive system, estrogens modulate insulin resistance, bone maintenance, muscle physiology, the cardiovascular system, and neoplastic processes. This chapter examines the process by which estrogens are delivered to the circulation and the intermediate metabolic processes that modulate their clearance and presentation to the microcirculation of target organs. It then integrates these principles into the clinical pharmacology of therapeutic estrogens.
|KINETICS OF ENDOGENOUS ESTROGENS|
Estrone (E1) and estradiol (E2) are classic estrogens that are heuristically the starting products in the expression of estrogen effect. Both steroids originate from ovarian secretion and from extraglandular aromatization of androgen precursors.1,2,3 The sites of El and E2 production depend on the stage of the menstrual cycle or on menopausal status.1,2,3 In reviewing this topic, it is necessary to define key terms frequently used to describe steroid kinetic interrelationships. These terms and the techniques used to measure them have been reviewed previously.1,2
Secretion rate (Sorgansteroid): Rate at which a steroid is secreted into the circulation by a specific steroid-synthesizing gland. The term secretion rate may be used in some circumstances to describe the total of secretion rates from all steroid-synthesizing glands.
(Blood) Production rate (PBBsteroid): Rate of steroid entry into the blood from all sources. It is the total amount derived from both glandular secretion and extraglandular conversion from other active hormones (e.g., E2 to El) or relatively inactive “prohormones” (e.g., androstenedione to [4A] to E1).
Metabolic clearance rate (MCR): Volume of plasma or blood from which a hormone is irreversibly removed per unit of time. The MCR is usually expressed in liters per 24 hours (liters/24 hr) or liters/24-hr/m2.
Transfer constant (pBBAB): Percentage of hormone “A” entering the blood per unit of time that is cleared and returned to the circulation as hormone “B” over an equal unit of time. For example: pBBE2E1 is 0.15; this means that 15% of E2 produced per unit of time is cleared and returned to the circulation as E1.
Estrogen Kinetics in the Premenopause
In premenopausal women, estrogen production and clearance are profoundly affected by the stage of the menstrual cycle.2 Accordingly, blood production rates (PBE2) and ovarian secretion rates (SovE2) for E2 are shown as a function of menstrual cycle days in Figure 1.2 For all phases of the cycle, approximately 95% or more of circulating E2 originates by direct secretion from the ovary containing the preovulatory follicle or corpus luteum.2 During menstruation, PBE2 is approximately 60 μg/24 hr, reaches approximately 400 μg/24 hr immediately before ovulation, and stabilizes at approximately 330 μg/24 hr during the midluteal phase.2 Mean MCRE2 is approximately 1300 liters/24 hr in menstruating women (Table 1).3,4 The PBBE1E2 is approximately 15%.3,4 Blood production rates (PBE2) and ovarian secretion rates (SovE2) for E1 are shown as a function of menstrual cycle days in Figure 2. As contrasted to E2, less than 50% of PBE1 is derived from ovarian secretion; during menses and at midcycle, the percent PBE1 derived from SovE2 is well under 30%.2 The major sources of El additive to SovE1 are conversion of secreted E2 to E1, 4A to El, and possibly direct adrenal secretion of E1. The substantial percentages of PBE1 derived from “other sources” at midcycle may represent additional peripherally converted 4A, which is known to peak at midcycle and is probably predominantly of ovarian origin.3 During menstruation, PBE1 is approximately 60 μg/24 hr, increases to 200 μg/24 hr immediately before ovulation, and reaches 150 to 380 μg/24 hr during the luteal phase, the time of maximum PBEE1 being shortly after ovulation.2 Mean MCRE1 is approximately 2200 liters/24 hr in menstruating women (see Table 1).1,2 The PBBE2E1 is approximately 5%.1,2
Estrogen Kinetics After Menopause
In postmenopause life, estrogen production and clearance become acylic and decline sharply.5 Nearly all E2 and El in the circulation of postmenopausal women is derived from extraglandular aromatization of testosterone (T) and 4A, respectively (see Table 1). PBE2 is approximately 12 μg/24 hr; MCRE2 decreases to 900 liters/24 hr; pBBTE2 has not been established.5 PBE1 is approximately 45 μg/24 hr; MCRE2 is 1600 liters/24 hr, and PBB4AE1, is about 2.5%.5,6 If 4APB4A is approximately 2000 μg/24 hr and PBB4AE1 is approximately 2.7%, this pathway can account for the bulk of the PBE1 of 45 μg/24 hr in postmenopausal women.5,6
Postmenopausal estrogen production is thus far less than what is observed during the menstrual cycle. Furthermore, estrogen does not enter the circulation in significant amounts from any of the endocrine glands. Increased body fat has been associated with increased extraglandular aromatization and increased circulating E2 and El concentrations.7 PBE1 exceeding the 40 μg/24 hr range has been associated with postmenopausal bleeding and endometrial hyperplasia.8 Thus, it is not surprising that obesity is associated with increasing risk of endometrial carcinoma.9
|REGULATION OF ESTROGEN EXPRESSION|
E2 availability to intracellular receptors is modulated by plasma-protein binding; estrone sulfate (E1S) conjugation; formation of metabolites, such as catechol estrogens, which may modulate estrogen-receptor interaction by acting as antiestrogens in some tissues, such as the endometrium, and estrogens in others, such as the nervous system; estrogen conjugation; microvascular extraction in target organs; and autoregulation in target cells. The roles of these metabolic regulators are reviewed next.
Plasma Protein Binding
Steroid hormones cross target tissues and microvascular membranes by passive diffusion.10 Their rate of transfer is regulated by the availability of nonprotein-bound steroid, which must compete between estrogen target tissue receptor proteins and plasma-binding proteins.10,11 E2 interaction with sex hormone binding globulin (SHBG), a high-affinity plasma glycoprotein, is about 38% of the total E2. Circulating E2 is also bound to albumin for another 60%. Of the total, only 3% is unbound and fully available.9 E1 is not strongly bound to plasma proteins and has a much higher MCR than E2. E1S is bound with high affinity to albumin, with 90% of E1S circulating in bound form.12 MCR of El and E2 is greatly influenced by protein binding. Whenever serum-binding capacity is increased, tissue extraction and MCR are proportionally decreased. Although SHBG is probably regulated primarily by growth hormone, which promotes its synthesis in the liver, and somatomedin C, which stimulates its extravasation and uptake in tissues, sex steroids are believed to have a modulating influence that is indirect and quantitatively somewhat less important.13 Accordingly, androgens decrease SHBG production in the liver such that the binding capacity in men is lower than in women. Estrogens and thyroid hormone increase SHBG production.13 Binding capacity is further increased in women with hyperthyroidism. in pregnancy. by exogenous estrogens. and by smoking.13 Thus, in patients with polycystic ovarian disease, SHBG is suppressed by excessive androgens, resulting in elevated free estrogen as well as elevated free testosterone levels, all of which act in concert to aggravate further the underlying pathophysiology of this disorder.14 Excess E2 bioavailability may be important in the pathogenesis of breast carcinoma because women who develop this disease have higher levels of unbound E2 and lower levels of SHBG than non-cancer-afflicted controls.15 E1S is also affected by protein binding. Very high binding affinities between E1S and albumin are responsible for the slow turnover of the E1S pool, low E1S MCR, and low E1S glomerular filtration.8
Estrone Sulfate Conjugation and the E1 S Pool
The interconversions between E2, El, and E1S are depicted in Figure 3. Transfer constants are given for each of these reversible interconversions. Although E2 is the biologically active hormone, E1 is the first step to biologic inactivation of E2. It is an obligatory intermediate leading to the formation of either E1S or to ring A (catechol) and ring D (estriol and epiestriol) estrogen metabolites (see Fig. 3) through nonreversible transformations.8 Although E1 binds with estrogen receptors, much of its biologic activity may involve intercellular conversion to E2.16 E1S becomes hormonally active after cleavage of the sulfate radical by the liver or other peripheral sites and in target tissues, which may have sulfatase activity that permits autoregulated conversion to El and E2 from E1S. Such autoregulated activity, occurring at the cell level in the endometrium, breasts, and neoplastic tissues, may vary with the time of the menstrual cycle.16
E1S is quantitatively the single most important plasma estrogen metabolite. Its relative importance is described by the respective transfer constants (pBBE1-E1S 0.54; pBBE2-E1S 0.65), which means that 54%. of E1 and 65% of E2 entering the blood is converted to E1S.8 Although these transformations are reversible, the transfer constants describing the opposite reaction (pBBE1S-E1 0.21; pBBE1S-E2 0.014) indicate that a smaller percentage of E1 is formed from E1S than El to E1S, and an almost insignificant amount of E2 is formed from E1S. E1S apparently is not secreted by any endocrine tissue because virtually all of its blood production can be accounted for by the conversions El-ElS and E2-ElS.8 The E1S pool is conceptualized as a large, slowly metabolized estrogen reservoir with 90% of its mass albumin bound with consequently low MCR (~150 liters/24 hr) and low renal clearance.8,12 PBE1S fluctuates with the menstrual cycle much as do its major precursors, El and E2; follicular phase PBE1S is ~95 μg/24 hr, whereas luteal phase PBE1S is ~ 180 μg/24 hr.8 ElS plasma concentrations are higher than any other known estrogen, with representative follicular phase values of 1000 pg/ml and luteal phase values of 1800 pg/ml.17,18,19 When plasma ElS concentrations (Fig. 4) are compared with E1 and E2 during the menstrual cycle, ElS concentrations appear to lag slightly behind the large rises and decreases of E2 by about 24 hours, an observation that probably results from the large size of the ElS pool, its low MCR, and its slow turnover.19
Even though ElS is not itself biologically active, E1 and E2 formed at the target tissue from E1S may be of major importance. Endometrium, for example, converts ElS to E1 and E2.11 Target tissue metabolic activity of this type cannot be measured by in vivo isotope dilution techniques, and as such the actual contribution of E1S to overall estrogen effect is difficult to assess.
Substantial quantities of ElS and estradiol sulfate are found in breast tissues of patients with mammary carcinoma (Fig. 5).20 ElS is converted at high percentage to E2 in different hormone-dependent mammary cancer cell lines, with very little or no conversion in hormone-independent mammary cancers.20 Progesterone provokes a decrease in E2 uptake in vitro.20 Accordingly, the control of the sulfatase and 17β-hydroxysteroid dehydrogenase activity may be important regulators in estrogen-sensitive neoplastic tissues.20
Estrogen Metabolites: Ring A (Catechol) and Ring D (Estriol and Epiestriol) Estrogens
Virtually all estrogen metabolites flow through El (Fig. 6) as the parent precursor. After formation of El, further metabolic transformation takes place through one of two major pathways: the ring A hydroxylated compounds (catechol estrogens)21 or ring D hydroxylated compounds (estriol and the epiestriols).22 The relationships are shown schematically in Figure 6. Quantitatively, these pathways are of approximately equal significance. They are mutually exclusive--that is, they do not convert into one another, and there are relatively few compounds metabolized concurrently as both ring A and ring D compounds. The hormonal effects of the ring A compounds are limited primarily to the central nervous system (CNS) and are antiestrogenic in other estrogen-sensitive tissues.21 The ring D compounds retain their estrogenic attributes but are less active than E2.23
The parent catechol estrogen compound is 2-hydroxyestrone, and its principal metabolite is 2-methoxyestrone. The term catechol is derived from the presence of two hydroxyl groups on the aromatic A ring, a structural feature in common with the catecholamines.21 A group of 4-hydroxyestrogens, also catechol estrogens, has been identified but is of comparatively minor quantitative importance compared with 2-hydroxyestrones. Although the conversion of El to 2-hydroxyestrone takes place primarily in the liver, it also occurs in the hypothalamus and other CNS tissues.24,25 The 2-hydroxylation of the parent classic estrogens in the CNS is of major importance because the derived 2-hydroxy estrogens compete with catecholamines for the enzyme catechol-O-methyltransferase.24,26 As highly efficient competitive inhibitors of catechol-O-methyltransferase, catechol estrogens interfere with metabolic degradation of catecholamines at specific CNS foci, resulting in prolonged catecholamine activity with the consequent release of hypothalamic releasing and inhibiting factors that are catecholamine modulated.26 An alternative CNS activity for the catechol estrogens is competition for CNS E2 receptors; in this role, the catechol estrogens act as antiestrogens.21
The catechol estrogens behave as antiestrogens in peripheral estrogen-sensitive tissues. The 2-hydroxy compounds have virtually no uterotropic activity yet have 20% to 50% the affinity for uterine estrogen receptors as does E2 itself.21 Thus, direction of E2 metabolism through the catechol pathway may greatly suppress the peripheral estrogenic activity of secreted E2.21
Plasma concentrations of 2-hydroxyestrone are slightly lower than E2, with a range of approximately 50 to 95 pg/ml.27 Urinary excretion of 2-hydroxyestrone observed over the menstrual cycle ranged from approximately 15 μg/24 hr, with highest values observed at midcycle and during the luteal phase (Fig. 7).28
A shift of estrogen metabolites to the catechol pathway occurs in patients with hyperthyroidism or anorexia nervosa, female athletes, and in women who smoke.29,30,31,32,33 A shift to ring D metabolites occurs in hypothyroidism30 and in obesity.31 Increased metabolism through catechol estrogens has been believed to be important in breast cancer pathogenesis,34 uterotropic functions,35 cigarette smoking,33 and exercise-induced amenorrhea.32
In competitive female athletes, serum levels of catechol estrogens are increased during strenuous exercise, suggesting that conversion to this non-uterotropic steroid could be a factor in the amenorrhea of these women.32 Premenopausal female smokers show significantly increased estrogen 2-hydroxylation expressed as increased 2-hydroxyestrone urinary excretion.33 This shunting of estrogen metabolites through the catechol pathway may be an important mechanism for their association with the antiestrogen effects of cigarette smoking.33 Thus, female smokers have an early natural menopause, a lower rate of cancer of the endometrium, and an increased risk of osteoporotic fractures.33,36 They have a reduced risk of benign breast disease, endometriosis, and uterine fibroids.37,38
RING D PATHWAY (ESTRIOL AND THE EPIESTRIOLS).
The principal ring D compound, estriol (E3), is derived by 16α-hydroxylation of E1 to form the intermediate, 16α-hydroxyestrone. The epiestriols comprise various 16- and 17-hydroxylated estrogens arrayed into an assortment of α and β configurations (see Fig. 6).22 Although E3 is the most abundant urinary estrogen, unconjugated E3 circulates in plasma at very low concentrations (7 to 11 pg/ml) because much of it is conjugated to glucuronides.39 Although unconjugated E3 is believed to have an estrogen potency comparable to E1, its very low concentration indicates that its hormonal effect is not substantial.
Estrogen Conjugates and Their Excretion
Estrogen metabolites formed from either the catechol pathway or ring D pathway are conjugated in the liver and kidneys with a glucosiduronate radical at various hydroxyl groups to form highly polar (water-soluble) estrogen glucuronides, which are excreted into the urine. E1 and E2 can also be conjugated directly and excreted by the same process. Some estrogen is excreted in feces.40,41 The details of these reactions have been reviewed extensively.40,41
Bioavailability of biologically active estrogen is affected by the distribution and permeability properties of the microvascular circulation in estrogen-responsive organs. Extraction efficiency in estrogen-sensitive tissues may thus be much higher than in non-estrogen-sensitive tissues. Thus, when human uteri are perfused in vitro with a lactated Ringer's solution containing physiologic concentrations of E1, E2, and E1S and compared with perfusion with human female serum, endometrial and myometrial estrogen extraction is much higher from the Ringer's solution because it is free of binding proteins. Also, endometrial extraction of unbound E1S and E1 greatly exceeds myometrial extraction.10 Extraction is most efficient in the luteal phase and in specimens with endometrial hyperplasia. 10,42 This is thought to occur because influxes of steroids are related to the surface area of the microcirculation, which changes during the menstrual cycle.
The final common pathway of estrogen hormone action is incorporation of E2 into the nuclear receptor complex. Target tissues (e.g., myometrium, endometrium, and CNS structures) modulate their response to circulating estrogen at the cell level by self-regulated reversible conversion of biologically active estrogens to relatively inactive ones before receptor interaction. Thus, human endometrial cells convert E2 to El by progesterone-stimulated 17β-estradiol dehydrogenase, which increases markedly in activity during the progesterone-dominant luteal phase.43 Conversely, endometrial sulfotransferase augments conversion of unconjugated E1 and E2 to their respective and inactive 3-sulfates.44 Like 17β-dehydrogenase, sulfotransferase activity increases during the luteal phase, when it produces increasing E1S, which does not bind to intracellular estrogen receptors. E1S is excreted back into the circulation and is associated with decreased nuclear estrogen-receptor complex formation during the luteal phase.43 A similar activity occurs in myometrial tissues.44 In breast carcinoma tissue, this interconversion may modulate the estrogen dependency of this disease.20
Analogous autoregulatory functions involving the catechol estrogens modulate catecholamine metabolism in the CNS. Although catecholamine formation is modified by various physiological and pathological conditions, the regulatory impact of catechol estrogens is not well understood.21
|KINETICS OF EXOGENOUS ESTROGEN|
Therapeutic estrogens, in a wide selection of both parenteral and oral preparations, have been under intense clinical investigation for many years. After oral administration, estrogens pass through the intestinal mucosa into the portal circulation and liver, where extensive intermediary metabolism occurs (first-pass effect).45,46 Parenteral estrogens differ significantly from oral estrogens in that they are delivered directly into the circulation and to target tissues without first-pass effect.46 Because of this difference, the profile of estrogens and metabolites delivered to target tissues differs substantially between oral and parenteral formulations. Furthermore, because estrogen first-pass affects production of lipoproteins, clotting factors, plasma proteins, and other liver products, estrogen-induced metabolic effects that are beneficial, such as cardioprotection, and deleterious, such as cholelithiasis and hypertension, may differ.45,46,47 Accordingly, comparative pharmacokinetics of different estrogen delivery systems are clinically relevant and have been investigated extensively.
Transdermal estrogens are available as patches, skin creams, and gels; injectable preparations are available as subcutaneous pellets, and vaginal preparations have been evaluated as solutions, tablets, and vaginal rings.
TRANSDERMAL DELIVERY SYSTEMS.
Approved for clinical use during the 1980s, transdermal patches (Estraderm) are now available, delivering 0.05 or 0.10 mg/day of E2. These patches deliver steroid directly into the circulation using a multilayered device (Fig. 8) that consists of an external membrane that prevents evaporation, a reservoir containing E2 dissolved in alcohol, a microporous membrane that releases E2 to the skin, an adhesive layer, and a protective film that is removed before application to protect the adhesive.45,46 The patch is reapplied every 3 days and provides immediate follicular phase E2 concentrations that remain stable for more than 80 hours. Absorption then dissipates quickly. When the patch is removed, serum levels of E2 decline immediately.47,48,49 Figure 9 illustrates serum levels of E2 after adding and removing the patch. The theoretical virtue of this system is that it delivers crystalline E-, into the circulation in a sustained, controlled fashion much as it would be delivered by the ovary. Because there is no first-pass effect, E2 is presented to target tissues as an arguable approximation of physiology without the pharmacologic effects on liver protein biosynthesis. Accordingly, as the E2 level rises, hot flashes are relieved, gonadotropins are suppressed, urinary calcium excretion is reduced, and bone density is maintained. Except for possible lipoprotein effects after a year or more of treatment, the system does not alter serum lipoproteins or clotting factors as do oral estrogens.47, 48, 49, 50, 51 Consequently, although the protective cardiovascular effects of oral estrogens from first-pass effect on lipoproteins may be lost, there may be decreased adverse effects on clotting factors, hypertension, and cholelithiasis.46 Considerable controversy surrounds the presence or absence of cardioprotective action.46
Percutaneous dosing with creams and gels has been investigated, but absorption is unpredictable and application is messy.52
Vaginal estrogens have been administered using polysiloxane rings, creams, solutions, and tablets.45 Vaginal dosing, because it also bypasses the liver, transmits its estrogen effects directly into the circulation. E2-impregnated polysiloxane vaginal rings have been extensively investigated.53 Vaginal rings containing from 100 to 400 mg of E2 produced follicular phase E2 concentrations ranging from 40 to 140 pg/ml.45, 53 Although this system produced stable and therapeutic levels of E2 in clinical studies, it never evolved into clinical practice. In one report, progesterone was administered through polysiloxane vaginal cylinders, making possible simulation of the entire normal menstrual cycle in agonadal women (Fig. 10).54 Progesterone delivery, however, required large and comparatively uncomfortable appliances and therefore did not achieve the acceptance reported with the E2 rings.54 Vaginal creams, fluids, and tablets, though investigated, have not provided the same predictable and stable serum E2 levels as the polysiloxane appliances. Vaginal creams, though widely used for treatment of vaginal atrophy in postmenopausal women, are not considered reliable for delivery of systemic estrogens.55
INJECTABLE ESTRADIOL AND SUBCUTANEOUS PELLETS.
Because estrogens are poorly soluble in water, estrogen esters in oil have been widely used. Some forms of E2 valerate and E2 cypionate remain active for a week or more after a single injection. They are sometimes abused for their placebo effect. E2 has also been administered subcutaneously in crystalline pellets. Pellets of 25 mg produced E2 concentrations ranging from 50 to 70 pg/ml, with 50-mg doses ranging from 100 to 120 pg/ml sustainable for several months.56, 57 Although the pellets are pharmacologically reliable, reinsertions were required every several months. They were also impossible to remove in the event of an adverse reaction and for this reason have not remained in clinical practice.
Four general groups of oral estrogens are in wide clinical use (Table 2): pure E1S used in agonadal and menopausal replacements; conjugated equine estrogens given with E1S used in agonadal and menopausal replacement therapy; micronized E2, also used in agonadal and menopausal replacement therapy; and the 17α-ethinyl compounds (ethinyl estradiol and mestranol) used in oral contraceptive formulations. The contents of these preparations, although entirely different from one another, exploit analogous intermediate metabolic principles in the expression of their clinical estrogen effect.
ESTRONE SULFATE AND CONJUGATED EQUINE ESTROGENS.
E1S and conjugated equine estrogens (see Table 2) are reviewed together. Crystalline E1 and E2 are virtually inactive when ingested orally. E1S (Ogen) or E1S administered as Premarin (E1S 70%, equilin sulfate 20%, equilin sulfate, and others) is a highly effective oral estrogen used clinically in agonadal and postmenopausal replacement therapy. E1S is absorbed through the gastrointestinal tract and passes into the E1S pool. From the E1S pool, sufficient amounts are hydroxylyzed to increase significantly the PBE1 and the PBE2 to exert a clinically useful estrogen effect.8 Additional estrogen effect is exerted at the target tissue cellular level, where E1S is converted to E1 and E2 probably through its mass action effect on the respective steroidogenic enzyme systems.43, 44 The pharmacodynamics of an average oral dose of ElS (0.5 mg) provide a useful illustration of the way this type of preparation works. Recalling that the PBE1S during the follicular phase of the cycle is 100 μg/24 hr, the orally administered dose of E1S at 0.5 mg (500 μg) is five times the normal follicular phase value. Assuming a PBBE1SE1 of 0.2 (see Fig. 3) and a molecular weight correction of 0.70 (E1S to E1) (0.5 × 0.7 × 0.2), the resulting PBE1 would be 70 μg/day. This is to be compared with an average endogenous PBE1 after menopause that is ~40 μg/day.8 On this background, it is interesting to recall that PBE1 of >40 μg/24 hr is associated with endometrial hyperplasia.8
Micronized E2 (Estrace) is a preparation in which the E2 crystals have been reduced to particles of 20 microns or less.58 This process increases surface area and facilitates intestinal absorption. Its oral effectiveness is attributed to rapid passage into the portal circulation. In traversing the intestinal mucosa quickly, however, a substantial portion of this substance is converted to E1. It is used clinically in agonadal and postmenopausal replacement. It has also been used with injected progesterone to support pregnancies from transplanted embryos.59 As shown in Figure 11, the maximum concentrations for E1 and E2 are reached between 2 and 6 hours after ingestion rather than immediately.58 This observation suggests that substantial amounts of micronized E2 enter and then leave the E1S pool gradually over time, thus, modest elevation in circulating E1 and E2 as well as gonadotropin suppression is still evident 24 hours after the dose. The standard dose of 2 mg (2000 μg) micronized E2 exceeds the combined follicular phase PBE2 of 80 μg/24 hr by about 20 times and the respective luteal phase values by approximately 2 times. Smoking induces significant changes in the serum binding of oral micronized E2.60 Unbound (non-SHBG-bound) E2 is significantly lower in smoking women because SHBG binding capacity is increased.60 Also, SHBG concentrations are higher in smoking women than in nonsmokers. Thus, in smoking women there may be less unbound E2 available to the microcirculation of target tissue. The difference does not appear to be sufficient, however, to justify modifying doses.60
17a-ETHINYL ESTROGENS: MESTRANOL AND ETHINYL ESTRADIOL.
Mestranol (ME) and ethinyl estradiol (EE) are important because of their widespread use in oral contraceptive formulations. Their molecular structures are shown in Figure 12, where it can be seen that both steroids have the same structural skeleton as E2 except for the ethinyl group at the 17α position; this feature renders 16α-hydroxylation difficult because of steric hindrance. ME differs from EE only by the introduction of a 3-methyl group. ME is biologically inactive unless demethylated at the 3 position, in which case it becomes EE.61, 62
The 17α-ethinylestrogens are the most potent estrogens known per unit mass, a feature that is probably related to the delay in de-ethinylating the 17α-ethinyl configuration. The principal metabolites formed from these steroids are therefore ring A hydroxylated compounds, the catechol estrogens.63, 64 The physiological impact of forming non-physiologic amounts of CNS-active catechol estrogens is not known.
The plasma concentrations of EE over time after doses of EE (50 to 80 μg) or ME (50 to 100 μg) are shown in Figure 13. Although EE concentrations rise to maximum levels immediately after the administration of EE, the ME dose produces a delayed and unpredictable increment in EE concentrations. The delay is presumably related to the demethylation required to convert ME to EE.65
Circulating EE equilibrates with a large EE sulfate (EES) pool analogous to the E1S pool. This provides a large reservoir of biologically inactive steroid, which is recirculated by hydrolysis of the sulfate radical.66 MCRME is ~1750 liters/24 hr, whereas MCREE is ~1350 liters/24 hr. The PBBME EE is ~18%.66 Circulating EE is thought to have a two-component half-life; the rapid half-life is about 7 hours, whereas the slow half-life is about 48 hours. The slow component may be related to re-entry of EE from the EES pool. Consequently, residual EE activity may remain for several days after a single dose.66, 67 Despite widespread use of EE, its serum levels are erratic and affected by the progestin to which it is dosed.68 Also, ethinyl estrogens accumulate in the liver, have an exaggerated effect on liver protein synthesis, and are not used in replacement therapy.68
The regulation of estrogen hormonal expression is complex far beyond the kinetics of secretion and target tissue receptor steroid interaction. Plasma binding, the pathway of metabolite formation, target organ microcirculation, and autoregulated target tissue responsiveness at the intracellular level are additional regulatory foci. The full clinical, diagnostic, and therapeutic impact of these mechanisms is far better understood today than when the previous edition of this chapter was published, but much remains to be learned.
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