Oral Administration
The relative potencies of commercially available estrogens are of great importance when prescribing estrogen, and the clinician should be familiar with the following potencies:
The 17α-ethinyl group of ethinyl estradiol (by resisting metabolism) enhances hepatic effects, because no matter by which route it is administered, liver function is affected.
13 The same is true for conjugated equine estrogens. Contrary to the case with estradiol, the liver appears to preferentially extract ethinyl estradiol and conjugated equine estrogens no matter what the route of administration. Thus, the route of administration appears to influence the metabolic responses only in the case of specific estrogens, most notably estradiol.
A major factor in the potency differences among the various estrogens (estradiol, estrone, estriol) is the length of time that the estrogen binds to its receptor. The higher rate of dissociation with the weak estrogen (estriol) can be compensated for by continuous application to allow prolonged binding and activity. Estriol has only 20-30% affinity for the estrogen receptor compared with estradiol; therefore, it is rapidly cleared from a cell. However, if the effective concentration is kept equivalent to that of estradiol, it can produce a similar biologic response.
16 At least two studies have been unable to demonstrate prevention of bone loss with the administration of 2 mg estriol daily.
17,18 In pregnancy, where the concentration of estriol is very great, it can be an important hormone not just a metabolite. Thus, higher estriol levels are not necessarily protective against potent estrogenic effects. Because estriol protects the rat against breast tumors induced by various chemical carcinogens,
19 it has been hypothesized that a higher estriol level protects against the more potent effects of estrone and estradiol. But, antagonism of estradiol occurs only within a vary narrow range of the ratio of estradiol to estriol, a range that is rarely encountered either physiologically or pharmacologically.
20 Below this range, estradiol is unimpeded, above this range estriol itself exerts estrogenic activity. The commercial preparation that contains estriol, estradiol, and estrone contains sufficient amounts of estrone and estradiol to produce standard clinical effects.
Esterified estrogens are synthetically prepared from plant precursors and are composed mostly of sodium estrone sulfate with a 6-15% component of sodium equilin sulfate. Estradiol valerate is rapidly hydrolyzed to estradiol; therefore, the pharmacology and effects are comparable at similar dosages.
21
Transdermal Patch Administration
The patches first used for transdermal estrogen administration contained an alcohol reservoir; the estrogen was released through a semipermeable membrane attached to the skin with an adhesive. In the current generation of patches, the hormones are dissolved and distributed throughout the adhesive matrix. In a study of women who had previously discontinued patches because of skin irritation (contact dermatitis), skin reactions were less common with the newer matrix patches.
22 In addition, the matrix patches are better tolerated in tropical environments.
23 The patches are designated according to the amount of estradiol delivered per day: from 14 to 100 μg.
The concentration of estrogen in the hepatic portal system after oral administration is 4-5 times higher than that in the periphery.
24 Because of first-pass metabolism in the liver, oral estradiol results in a circulating estrone to estradiol ratio of approximately 3; with transdermal administration the ratio is 1. The first-pass effect may be important for lipoprotein effects. For example, short-term studies (6 weeks) could document increased catabolism of low-density lipoprotein (LDL-cholesterol) and increased production of apoprotein A-I with oral estrogen, but no effect with transdermal estrogen.
25,26 A 2-year study in Los Angeles with a transdermal dose (100 μg) detected no significant change in HDL-cholesterol levels.
27 However, English data indicate that the transdermal administration of 50 μg estradiol twice a week is as effective as 0.625 mg oral conjugated estrogens, when combined with a progestin in sequential regimens, on bone density and lipids over a duration of 3 years.
28 Standard doses of estrogen administered transdermally (50 μg) protect against fractures as well as standard oral doses do.
29 As with oral estrogen, lower transdermal doses can produce effects on bone density and menopausal symptoms,
30 but a substantial number of women require higher doses.
The critical question is whether the first-pass effect of oral estrogen is clinically important. The different effects of oral and transdermal administration on metabolic parameters have been repeatedly compared over the years, but epidemiologic studies of clinical end points are not abundant, handicapped by the relatively small numbers of women using transdermal estrogen in most countries.
Clotting Factors. First-pass hepatic metabolism affects the synthesis of clotting proteins, markers of coagulation and fibrinolysis that can influence the risk of thrombosis and coronary heart disease events. Oral estrogen increases factor VII and prothrombin 1 and 2 fragment, whereas transdermal estrogen decreases factor VII.
31,32,33 and
34 Oral estrogen also increases circulating levels of matrix metalloproteinases, MMP-2 and MMP-9, enzymes that are associated with a tendency for clotting.
35 However, what is important is whether the different effects of oral and transdermal delivery on clotting factors translate into clinical differences and cardiovascular risk.
Activated Protein C (APC) Resistance and Risk of VTE. Resistance to APC is an important marker for venous thrombosis in individuals with inherited thrombogenic mutations and even in the absence of these mutations. Oral estrogen increases APC resistance, whereas transdermal estrogen has no significant effect on this marker.
36,37 Based on this difference, one would predict that transdermal delivery of estrogen would be less likely than oral delivery of estrogen to be associated with venous thromboembolism (VTE).
A French case-control study (epidemiologic studies of the link between the transdermal route of administration and a relatively rare event are possible in France because of the popularity of the transdermal method) reported no increased risk of VTE in users of transdermal estrogen, as compared with a 4-fold increase in oral estrogen users.
38,39 and
40 Estrogen users who carried a factor V Leiden mutation or a prothrombin mutation had a 25-fold higher risk of VTE than did women who did not use estrogen and did not have either mutation. The women with a prothrombotic mutation who used transdermal estrogen had a VTE risk that was similar to that of women with a prothrombotic mutation who did not use estrogen. The French E3N
prospective cohort study also reported an increased risk of venous thromboembolism with current users of oral therapy, a hazard ratio of 1.7 (CI=1.1-2.8), a ratio that is similar to the usual 2-fold increase repeatedly documented in the literature, and no increase with transdermal estrogen.
41 Venous thrombosis is discussed in more detail later in this chapter.
Lipids and Hepatic Enzymes. Both oral and transdermal estrogen reduce total cholesterol, low-density lipoprotein cholesterol, and lipoprotein(a). Compared with transdermal estrogen, oral estrogen produces significantly greater elevations in high-density lipoprotein cholesterol and increases triglycerides, whereas transdermal estrogen decreases triglyceride levels.
31,33,42,43 and
44 Indeed, triglyceride levels markedly elevated in response to oral therapy return to normal when treatment is changed to transdermal administration.
45
Inflammatory Markers. Women on oral estrogen have increased levels of C-reactive protein (CRP), whereas those taking transdermal estrogen do not.
31,33,42,46,47,48 and
49 In fact oral hormone therapy while increasing CRP, as discussed in
Chapter 17, reduces the circulating levels of other inflammatory markers (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-α) with inconsistent effects on interleukin-6.
46,47 Transdermal estrogen does not affect levels of these inflammatory markers. It is not certain that the decrease in CRP levels with statins and the increase with oral estrogen are instrumental in clinical outcomes or reflect other effects. Thus raising or lowering CRP levels will not necessarily increase and decrease the risk of clinical disease.
A longitudinal study of 346 postmenopausal women taking oral hormone therapy reported that elevated CRP was a strong predictor of future cardiac events, but only in those with increased IL-6 levels.
48 An increase in CRP alone was not associated with an excess of events.
The difference in CRP levels between users of oral versus transdermal therapy, especially in younger postmenopausal women, is of little clinical significance. In fact, in the Estrogen Replacement on Progression of Coronary Atherosclerosis trial, estrogen-induced increases in CRP had no effect on disease progression, as measured by serial angiograms.
49 A study from the Women’s Health Initiative confirmed the correlation between baseline levels of CRP and an elevated risk of coronary heart disease,
but the increase in CRP induced by oral hormone therapy did not further increase the risk!50
Myocardial Infarction Risk. Both oral and transdermal administration of hormone therapy are associated with a decrease in myocardial infarction risk in observational studies.
51
Metabolic Syndrome. In a 3-month randomized trial involving 50 obese women with metabolic syndrome, oral estradiol therapy worsened markers of the metabolic syndrome, including insulin resistance, suggesting a worsening of cardiovascular risk, whereas transdermal estradiol had minimal effects.
52
Effects in Smokers. Limited evidence suggests that postmenopausal women who smoke may have a better cardiovascular response to transdermal estrogen than to oral estrogen, including greater reductions in total peripheral resistance, vascular sympathetic tone, and norepinephrine levels, and increased vascular responsivity.
53 Smokers receiving transdermal estradiol have decreased plasma viscosity and thromboxane B
2 levels.
54 These results raise the possibility, although the data are limited, that smokers may represent a group of women for whom transdermal estrogen would be an advantage.
Carbohydrate Metabolism. There is little difference between the oral and transdermal methods of delivery on carbohydrate metabolism. Both methods have a beneficial impact on central abdominal fat content, glucose levels and insulin resistance, associated with a reduced risk of developing adult-onset diabetes mellitus.
55,56,57,58 and
59
Breast Cancer Risk. Oral conjugated equine estrogens/sequential medroxyprogesterone acetate decreased median levels of insulin-like growth factor-1 (IGF-1) by 26% and
increased median levels of sex hormone-binding globulin (SHBG) by 96% relative to baseline, whereas no change occurred with transdermal estradiol.
60 High IGF-1 and low SHBG levels are associated with increased breast cancer risk; however, it is difficult to make clinical conclusions based on these secondary markers. A German case-control study of 3,593 cases found no significantly increased risk of breast cancer with oral or transdermal hormone therapy.
61 Thus far, the epidemiologic data comparing oral and transdermal treatment are not sufficient to allow firm conclusions regarding breast cancer risk.
Colorectal Cancer Risk. In a case-control study, both oral and transdermal hormone therapy reduced the risk for developing colorectal cancer.
62 When transdermal therapy involved estrogen alone, the benefit was even greater.
Estradiol Levels in Users of Oral Versus Transdermal Estrogen. Studies comparing circulating estradiol levels in women receiving oral or transdermal estrogen reveal therapeutic estradiol levels predictive of a good bone response, but they also contain large standard deviations, indicating substantial variation among individuals.
63 Individual women metabolize estrogen differently, depending on the route of administration, liver function, skin absorption, body composition, body size, potential medication interactions, and the presence of binding proteins; all of which contribute to individual variations in serum estradiol levels.
64 In the future, measurement of serum estradiol levels may play a role in assessment of adequate treatment. This measurement will be especially useful for users of transdermal estrogen therapy, which produces more consistent estradiol levels than does orally administered therapy.
The only way to accurately compare clinical differences between oral and transdermal estrogen delivery is to establish that the two methods produce similar blood levels and that clinical differences reflect the first-pass effect through the liver. This is difficult to accomplish because the oral first-pass effect raises sex hormone-binding globulin (SHBG) levels such that total serum estradiol levels are greatly affected. A study of 18 women showed that oral estrogen increased SHBG by 67% to 171%, whereas transdermal estrogen did not alter SHGB levels.
65 Estrogen-induced changes in SHBG may be clinically significant because estrogen unbound to SHBG determines the estrogen effects of a given regimen. The only study that measured free estradiol levels, compensating for increases in SHBG, indicated at 12 weeks, that serum free estradiol levels in the oral group were similar to those in the transdermal group.
32 However, because these results were derived from only 18 women, the effect of oral and transdermal doses on free estradiol levels has not been reliably established. A potential advantage of transdermal treatment because it has no effect on SHGB levels is the absence of a reduction in free, unbound testosterone levels as is observed with oral therapy.
63 Thus, the transdermal method may be indicated in women with impaired sexual function.
Oral Versus Transdermal Administration. It is difficult to draw conclusions about clinical differences between oral and transdermal hormone delivery based on secondary markers. Epidemiologic studies on clinical events are needed. However, this is a challenge because of the relatively small number of women receiving transdermal estrogen. In addition, the studies must adjust for individual variability of dosing to ensure that circulating estrogen levels in the patients being studied are similar.
The Vaginal Administration of Estrogen—Very Low-Dose Method
Some patients do not gain full relief from the symptoms of vaginal atrophy with oral or transdermal administration of estrogen. Local vaginal administration makes sense for these patients. Vaginal treatment is especially helpful when a rapid response is desired. In addition, there are many women who desire the genitourinary effects of estrogen but either must or wish to avoid systemic therapy. Overall, there is no evidence that one method or preparation is superior to the others in achieving clinical response.
Measurement of vaginal pH from the lateral vaginal wall is a simple and inexpensive way to assess adequate treatment of the vagina. It has been impressive in our experience and others how an acidic pH (<4.5) obtained from the lateral, outer third of the vagina correlates well with good estrogen effects.66,67 and 68
Many clinicians believe that estrogen administered intravaginally is not absorbed, and systemic effects can be avoided. This is not the case. Estrogen in creams is absorbed very readily from a vagina with immature, atrophic mucosa.
69 Indeed, the initial absorption is rapid, and relatively high circulating levels of estrogen are easily reached. As the vaginal mucosa matures, absorption decreases.
70 This decline takes approximately 3-4 months, after which lesser but still significant absorption takes place.
71 Effective treatment of vaginal atrophy with minimal absorption can be achieved with the administration of 0.3 mg conjugated estrogens, 2-3 times per week.
72,73 We believe that treatment with a vaginal cream longer than 6-12 months requires endometrial surveillance.
The amount of estradiol delivered in low-dose tablet form or a ring is not sufficient to treat menopausal symptoms, but effectively improves local urogenital atrophy and reduces recurrent urinary tract infections. This has been accepted as a method to relieve atrophic vaginal symptoms in women with contraindications to estrogen treatment; however, systemic effects do occur.
Estring is a 55-mm diameter silicone ring that contains 2 mg estradiol, with a release rate of 7.5 μg/day for 90 days.
74 European studies have demonstrated that vaginal maturation can be achieved with this ring that can be left in place for 3 months, with a low-level of systemic absorption.
75,76 The subjective symptoms associated with vaginal atrophy are rapidly relieved. No change in endometrial thickness was observed after 1 year of treatment.
77
Vagifem is a tablet that contains 25 μg estradiol, and the initial dose of 1 tablet daily produces relief from atrophic symptoms within 2 weeks.
78 After the first 2 weeks, the maintenance dose is twice weekly, and endometrial thickness has been reported to not change from baseline; however, the study was only 6 months in duration.
79 One 2-month study found no evidence of endometrial stimulation; another reported 1 case of vaginal bleeding with endometrial proliferation.
80,81 A smaller dose tablet, 10 μg, also improves vaginal atrophy, but it is not as effective as the larger dose.
82
The systemic absorption of estrogen from the low-dose estradiol ring or tablet is very low, especially after the vagina achieves estrogen-induced maturation (about 3 months). Is this low level of absorption free of the risk of endometrial hyperplasia? The problem is that all studies
have been too short (all 1 year or less, except one 2-year study) to determine long-term endometrial safety. Although systemic absorption occurs, the circulating estradiol levels with these low-dose methods remain in the normal postmenopausal range.
74,79,83,84,85 and
86 But, because the small increase in circulating estradiol levels causes distant target tissue responses (e.g., an increase in bone density or an improvement in the lipid profile
87,88), clinicians cannot assure patients that these methods are totally free of systemic activity.
Although the change in blood levels is very slight, and for that reason not effective for the relief of vasomotor symptoms, we believe long-term treatment requires ultrasonographic monitoring of endometrial thickness with biopsy when indicated. This ultrasonographic approach is more preferable than complicating the treatment regimen with the addition of a progestational agent. We further suggest that each patient titrate her dose and schedule of treatment to balance an effective response with minimal dosing. For women who are breast cancer survivors and are considering this treatment, clinicians and patients must accept a small but real unknown risk.
Monitoring Estrogen Dosage with Estradiol Blood Levels
Monitoring the estradiol blood level in postmenopausal women receiving hormone therapy is not as straightforward as it would seem. There are two primary difficulties. First, the clinical assays available differ considerably in their technique and quality (laboratory and antibody variations). Second, the various commercial products represent a diverse collection of estrogenic compounds, ranging from estradiol to unique equine estrogens. Although the body interconverts various estrogens into estrone and estradiol, is this process relatively consistent within and between individuals? A highly specific assay for estradiol will detect very low levels of estradiol in women receiving 0.625 mg conjugated equine estrogens; nevertheless, most clinical assays will report a level of 40-100 pg/mL in these women.
We find measurement of blood estradiol levels very useful in selected patients, such as the patient who requests ever-increasing doses of estrogen for the treatment of symptoms, which in the presence of very high blood levels of estradiol can be confidently diagnosed as psychosomatic. We further advocate titering of estrogen dosage with blood estradiol levels in women who fail to demonstrate a positive bone response on treatment, as discussed in
Chapter 17. What each clinician must do is learn what blood level of estradiol as performed by the local laboratory is associated with the standard doses of hormone therapy (0.625 conjugated estrogens, 1 mg estradiol, 50 μg transdermal estradiol) and consistently use the same laboratory. In our laboratory this range is 40-100 pg/mL estradiol when the estrogen is taken the evening before the office visit (with transdermal administration blood sampling should be obtained the day before new patch placement); the range reflects individual variation including the variability from peak to nadir values.
Remember that because FSH is regulated by a factor other than estrogen (i.e., inhibin), FSH levels cannot be used to monitor estrogen dosage. Postmenopausal hormone therapy will produce only a 10-20% decrease in FSH and LH, and there is great individual variability in the responses.
96
Products containing ethinyl estradiol will not affect the measurement of circulating estradiol levels. Ethinyl estradiol circulates without being changed, and the antibodies in the immunoassays for estradiol will not recognize it. It is for this reason that women on oral contraceptives have very low measurements of estradiol. This problem for the postmenopausal use of ethinyl estradiol is not a major handicap because ethinyl estradiol is slowly metabolized, and blood levels are relatively stable with less variation from individual to individual compared with the other estrogen formulations.
Estrogen-Progestin Sequential and Continuous Regimens
Postmenopausal hormone therapy initially consisted only of sequential regimens that were logical reflections of the cyclic estrogen and progesterone patterns in a premenopausal menstrual cycle. Clinical trials established the doses and durations for progestin administration that would effectively protect the endometrium against unchecked proliferation.
97 Progestin withdrawal bleeding occurs in 80-90% of women on a sequential regimen,
98,99 and
100 and for this reason the continuous combined method of treatment evolved to improve patient continuance that was adversely affected by bleeding and other symptoms triggered
by the cyclic hormonal changes. The addition of a daily dose of a progestin to the daily administration of estrogen allowed the progestin dose to be smaller, provided effective protection against endometrial hyperplasia, and resulted in amenorrhea within 1 year of treatment in 80-90% of patients.
99,101,102 and
103
In the sequential regimen, estrogen is administered daily and progestins for 2 weeks of every month, using the
comparable doses of the following progestins
100,101,104,105:
5 mg medroxyprogesterone acetate, or 0.7 mg norethindrone, or 1.0 mg norethindrone acetate, or 200 mg micronized progesterone.
In the daily continuous, combined regimen, progestins are combined with estrogen in the following
comparable doses
102,103,106:
1.5 or 2.5 mg medroxyprogesterone acetate, or
0.35 mg norethindrone, or
0.5 or 1.0 mg norethindrone acetate (0.1 mg dose is available), or
100 mg micronized progesterone or
2 mg drospirenone or
2 mg dienogest.
These hormonal regimens are combined with daily calcium supplementation (500 mg with a meal) and vitamin D (1,000-2,000 IU daily).
There has been a progressive decrease in dose used for postmenopausal hormone therapy. For many years, the standard dose of estrogen was 0.625 mg conjugated estrogens, 1-2 mg micronized estradiol, 1-2 mg estradiol valerate, or equivalent doses of other estrogens such as 5 μg ethinyl estradiol. Lower doses have been proven
on the average to be as effective as these “standard” doses, providing clinicians and patients with more options. Conjugated estrogens in a dose of 0.3 or 0.45 mg effectively produce a gain in bone density when combined with 1.5 mg medroxyprogesterone acetate, and a dose of 0.5 mg micronized estradiol produces comparable effects.
107,108,109 and
110 The 0.45/1.5 mg and 0.3/1.5 mg conjugated estrogens/medroxyprogesterone acetate combinations improve vaginal atrophy, reduce hot flushing, and improve measures of sexual function in a pattern that is quantitatively and qualitatively similar to the 0.625/2.5 mg combination with less mastalgia.
111,112 These lower-dose combinations are associated with less breakthrough bleeding and a higher rate of cumulative amenorrhea compared with older standard doses and retain the favorable changes in the lipid profile.
113,114 At these lower doses of conjugated estrogens, the combination with progestin produces an additive effect; therefore, when these lower doses of estrogen are used without progestin, the effect on hot flushing will not be as great. In a dose-response study, the most efficacious dose of oral micronized estradiol was 1 mg/day.
115 The lower-dose combination of ethinyl estradiol and norethindrone acetate (2.5 μg/0.5 mg) is nearly as effective in treating hot flushes as the higher dose combination (5.0 μg/1.0 mg).
116
Keep in mind our concern that with lower doses there will be more women who respond poorly, probably because of a greater rate of metabolism and clearance (discussed in Chapter 17).
Two metabolites of progesterone, allopregnanolone and pregnanolone, are believed to be responsible for progesterone’s unique sedative effect. Treatment regimens with micronized progesterone should be taken at bedtime, and these estrogen-progesterone combinations are a good choice for women with sleep difficulties. A study in a sleep laboratory has demonstrated a significant improvement in sleep quantity and quality in women using a
sequential regimen of estrogen and micronized progesterone in contrast to no effect in the group using medroxyprogesterone acetate.
117
Progestational Side Effects
Many women do not tolerate treatment with progestational hormones. Typical side effects include breast tenderness, bloating, and depression. These reactions are significant detrimental factors with continuance. However, appropriately designed, placebo-controlled studies fail to document adverse physical or psychological effects with short-term treatment utilizing medroxyprogesterone acetate, except for breast discomfort.
118,119,120 and
121 This suggests that progestin side effects other than mastalgia are related to duration of treatment or that only studies with large numbers of subjects will detect the small percentage of women who have problems (and both explanations are probably true).
Breast discomfort associated with postmenopausal hormone therapy can be attributed largely to progestins. In the PEPI randomized trial, an increase in mastalgia was observed
only in 28.7% of the women receiving estrogen-progestin combinations, containing either medroxyprogesterone acetate or progesterone.
120 Comparison studies have not been performed to address whether this symptom is minimized by particular progestins. It has been our experience, that changing to a regimen containing norethindrone or norethindrone acetate has been beneficial (but this may reflect either a placebo response or diminishing severity with time).
Can the progestational agent be administered less frequently? We are secure in our position, supported by clinical data, that a daily combination program effectively prevents endometrial hyperplasia. A sequential regimen that incorporates progestin exposure for less than 14 days has over time an increased risk of endometrial hyperplasia.
122,123 In a Finnish study, sequential regimens in standard schedules used for at least 5 years were associated with an increased risk of endometrial cancer.
124 Thus, sequential regimens with less than 14 days of progestin monthly or
even long-term use of recommended schedules do not match the protection offered by the daily, continuous method of estrogen-progestin treatment.
Experience with extended cycle regimens is very limited. The administration of medroxyprogesterone acetate every 3 months was associated in 1 study with longer, heavier menses and unscheduled bleeding and a 1.5% incidence of hyperplasia at 1 year, whereas in another study, overall bleeding was less, but the incidence of hyperplasia was approximately 4%.
125,126 In a Dutch study that was only 12 weeks in length, simple endometrial hyperplasia was encountered at the end of the unopposed estrogen phase.
127 In yet another study, there was no endometrial hyperplasia encountered by 143 women who completed 2 years of treatment; however, the progestin administered every 3 months was of high dosage, 20 mg medroxyprogesterone acetate daily for 14 days.
128 In Finland, the addition of progestin at 3-month intervals was associated with a striking increase in the risk of endometrial cancer when this regimen was used for many years.
124 Most impressively, the Scandinavian Long Cycle Study, a clinical trial scheduled to last 5 years, was canceled after 3 years because of a 12.5% incidence of endometrial pathology and 1 case of endometrial cancer.
129 Therefore, if a patient chooses an extended cycle regimen, endometrial monitoring is required.
In our view, an annual endometrial biopsy is strongly recommended in estrogen users exposed only intermittently to progestin treatment. Any program that differs from the standard regimen is untested by clinical studies of sufficient length and patient numbers and, therefore, requires periodic surveillance of the endometrium. Even the long-term use of standard sequential regimens is subject to a small increase in the risk for endometrial cancer, and endometrial surveillance should be considered in women using this method.
Some patients are very sensitive to medroxyprogesterone acetate. In our experience, these patients are often relieved of their symptoms by switching to norethindrone. In a sequential regimen, the dose of norethindrone is 0.7 mg (available in the progestin-only, minipill oral contraceptive; each pill contains 0.35 mg norethindrone). In the continuous, combined regimen, the dose of norethindrone is 0.35 mg daily. Commercial combination products are available containing estradiol and norethindrone acetate.
Progesterone can be administered in a vaginal gel that allows the delivery of very low doses that can effectively protect the endometrium with low systemic levels because of a first-pass effect on the uterus.
130 The administration of 90 mg every 2 days produces secretory changes in the endometrium.
131 An application of the 4% commercial preparation twice weekly protects the endometrium and is associated with amenorrhea in most patients. In a sequential regimen, the 4% preparation should be applied daily for at least 14 days each month. No long-term studies are available that document endometrial safety and metabolic effects.
The transdermal estrogen-progestin combinations incorporate norethindrone acetate in a daily dose of 0.140 or 0.250 mg; or levonorgestrel in daily doses of 0.007, 0.015, 0.030, and 0.040 mg/day; and in a sequential regimen, norethindrone acetate, 0.250 mg, or levonorgestrel, 0.010 mg.
132,133 and
134