By
Jeffrey T. Jensen, MD, MPH
Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports he is a consultant for, on the Advisory Boards of, and receives grant/research support from HRA Pharma, Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, Evofem, and ContraMed; and he is a consultant for Teva Pharmaceuticals and MicroChips.
After a lost decade, increasing numbers of women and providers are recognizing the benefits of postmenopausal hormonal therapy. For women with an intact uterus, endometrial protection is required when systemic estrogen therapy is used. Since activity at the glucocorticoid and androgen receptor may lead to adverse health effects in some women, use of pure progesterone receptor agonists may offer advantages. However, the use of natural progesterone is problematic due to low potency and poor bioavailability with oral dosing. Local therapy with the levonorgestrel intrauterine device (off-label) may be an excellent choice for many women.
We are seeing a slow movement back to postmenopausal hormone replacement therapy (HRT) after the dark years following publication of the original Womens’ Health Initiative (WHI) reports in 2002. The 2014 revision of the American Congress of Obstetricians and Gynecologists Practice Bulletin for management of menopausal symptoms provides a balanced discussion of benefits and risks of HRT that places the WHI findings in perspective with other literature.1 As in the past, the discussion is often initiated by women in response to symptoms of hot flushing and vaginal dryness. While hot flushing goes away in most women, and vaginal dryness can be treated with topical estrogens and lubricants, many women are interested in systemic therapy. Although the pharmaceutical industry continues to chiefly explore and promote costly new non-estrogen options for systemic therapy (e.g., ospemifene, basodoxiphene), I remain convinced that good old-fashioned estradiol is the best approach, as long as the oral route of administration is avoided. The primary risk of estrogen is an increased risk of thrombosis,2 and bypassing the liver with transdermal or vaginal administration of estrogen avoids this first pass metabolism and mitigates the risk.3
Unfortunately, unopposed estrogen administration will result in endometrial hyperplasia and cancer in some women. It has long been known that co-treatment with a progestogen prevents this. Progestogens mediate their effect by modulating gene transcription through binding not only to the progesterone receptor (PR), but also with varying affinities to the glucocorticoid (GR), mineralocorticoid (MR), and androgen (AR) receptors. Side effects are thought to be related to binding of a progestogen to GR, AR, and MR. A variety of factors (e.g., route of delivery, metabolism, serum protein binding) will also affect the bioavailability of the active form of a progestogen at target cells.4 An ideal progestogen would have pure PR activity with great bioavailability and high potency, but no AR, GR, or MR activity. However, some progestogens have tissue-specific effects or are antagonists of other steroid receptors, complicating the picture further.
Progestogens can be divided into two types: natural (progesterone) and synthetic (everything else). Synthetic progestogens are classified according to the steroid hormone scaffold (progesterone or testosterone) on which the molecule is based. Drospirenone is unique in that it is structurally related to spironolactone.5 A wide variety of compounds that differ in their relative oral bioavailability and binding to the PR, AR, GR, and MR have been synthesized and used in HRT.
The most widely used agent in HRT has been medroxyprogesterone acetate (MPA). The primary advantage of MPA is its high bioavailability with oral administration (> 90%), potency, and a 24-hour half-life compatible with once-daily dosing.5 Evidence suggesting that MPA may attenuate the favorable effects of oral estrogens on lipids first emerged in the 1995 PEPI study,6 and was later supported by the increase in cardiovascular disease and invasive breast cancer observed in the WHI among women using combined HRT (conjugated equine estrogens [CEE] + MPA) but not in women using CEE alone.7 Some of the unfavorable properties of MPA are thought to be associated with binding to the GR, where it displays significantly higher binding affinity than cortisol.5 The unfavorable effect of MPA on breast cancer may also be mediated through the GR.5 Unfavorable effects on lipids and on blood flow have also been reported with MPA.
Table 1: Classification of Progestogens
|
Classification |
Progestogen |
|
Natural
|
Progesterone
|
|
Synthetic
|
|
Structurally related to progesterone
|
|
Pregnane derivatives
|
|
Acetylated
|
MPA, megestrol acetate, chlormadinone acetate, cyproterone acetate
|
|
Nonacetylated
|
Dydrogesterone, medrogestone
|
|
19-Norpregnane derivatives
|
|
Acetylated
|
Nomegestrol acetate, nestorone
|
|
Nonacetylated
|
Demegestone, promegestone, trimegestone
|
|
Structurally related to testosterone
|
|
Ethinylated
|
|
Estranes
|
Norethindrone, norethindrone acetate, ethynodiol diacetate, norethynodrel, lynestrenol, tibolone
|
|
Gonanes
|
Levonorgestrel, desogestrel, norgestimate, gestodene
|
|
Nonethinylated
|
Dienogest
|
|
Structurally related to spironolactone
|
Drospirenone
|
|
Adapted from: Sanzek FZ, et al. Progestogens used in postmenopausal hormone therapy: Differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev 2013;34:171-208.
|
In contrast, natural progesterone has poor oral bioavailability of < 5% and a half-life of about 16 hours.5 Consequently, a much higher dose (200 mg micronized progesterone) is recommended for endometrial protection. Some women will be fine with a dose of 100 mg/day, while others will need to use 200 mg or divide that dose into twice daily. The fact that there is no FDA-approved topical progesterone product reflects the fact that bioavailability varies greatly. Serum levels of progesterone did not exceed 3.5 mg/mL when creams delivering up to 80 mg per day were used by postmenopausal women; levels > 5 ng/mL are considered protective for the endometrium.8 Progesterone gels result in higher serum levels that might be protective. If your patients are using a progesterone gel or cream prescribed by a naturopath, recognize that these are formulated by compounding pharmacists and may not be uniform. Doses of at least 100 mg/day would be recommended. It would be wise to obtain a serum progesterone level to guide therapy, and an endometrial stripe measurement by transvaginal ultrasound should be strongly considered.
The commercially available 4% vaginal progesterone gel (Crinone®) has been evaluated for endometrial protection in combination with transdermal estradiol. This product delivers 45 mg/day, and no cases of endometrial proliferation were observed in a small study involving 35 subjects. However, this is not approved for HRT and is quite expensive.
Combination transdermal systems releasing levonorgestrel (Climara Pro™) and norethindrone acetate (CombiPatch™) are also available. Clinical trials support endometrial protection with both products. As with oral therapy, breakthrough bleeding can occur with these products. This can scare patients and lead many providers to perform unnecessary endometrial biopsies. Since neither norethindrone nor levonorgestrel binds to the GR, no effect on the breast would be expected.5 Many women appreciate the convenience of using a single product for HRT rather than combining a patch or gel for estrogen replacement therapy (ERT) with a different route of administration for the progestogen.
Since reducing systemic AR, MR, and GR exposure from progestogen therapy might be an important goal of therapy, intrauterine administration may provide several benefits. The 5-year, 20 mcg/day release rate levonorgestrel intrauterine system (LNGIUS 52, Mirena™) is approved for contraception and treatment of heavy menstrual bleeding. In a pooled analysis, the LNGIUS 52 was highly effective at providing endometrial protection during ERT; proliferative endometrium was not observed at 2-5 years of use, whereas 11.1% of samples in a comparator group using oral LNG 75 mg were proliferative at 2 years.9 Additional studies with transdermal and vaginal estrogen have confirmed these early results. Among postmenopausal women randomized to estradiol gel (1.5 mg/day) combined with either the LNGIUS 52 or progesterone (100 mg on days 1-25) administered orally or vaginally (n = 15), all LNGIUS users had inactive or atrophic endometrium, compared to only 21% and 33% of women in the oral and vaginal groups, respectively.9 Similar to premenopausal women using the LNGIUS for contraception, breakthrough bleeding and spotting is most common during the first 3 months of use and then decreases, with 80-96% experiencing amenorrhea after 12 months.9 Endometrial protection has also been reported with the use of an experimental LNGIUS releasing 10 mcg/day. Although the recently introduced 12 mcg/day small frame LNGIUS 13.5 (Skyla™) has not been studied for endometrial protection, it would be expected to have a similar effect. Furthermore, the smaller frame and insertion tube diameter of this device may make it especially well-suited for placement in postmenopausal women. The great advantage of the LNGIUS is the local delivery of LNG. Systemic circulating levels of drug are lower than with oral, vaginal, or transdermal delivery, so metabolic impact and adverse effects should be reduced if these are exposure-related.
A major barrier to the use of the LNGIUS for endometrial protection is the lack of FDA approval for this indication. For many women, the cost of the device and placement is not affordable without insurance coverage. Other women will look at the convenience and cost-effectiveness and consider this off-label use a justifiable investment, so I always present the option in counseling. The easiest women to start on this approach are recently menopausal women with a current LNGIUS that was placed for contraception.
References
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Canonico M, et al. Circulation 2007;115:840-845.
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Hapgood JP, et al. J Steroid Biochem Mol Biol 2014;142:39-47.
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Stanczyk FZ, et al. Endocr Rev 2013;34:171-208.
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The Writing Group for the PEPI Trial. JAMA 1995;273:199-208.
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LaCroix AZ, et al. JAMA 2011;305:1305-1314.
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Stanczyk FZ, et al. Menopause 2005;12:232-237.
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Depypere H, Inki P. Climacteric 2015:1-32.
