Current issues in hormone therapy: A 3-part CME series ObGyns frequently address patient concerns about the safety of hormone therapy (HT) in managing their postmenopausal symptoms. In this case-based CME newsletter series, Robert D. Langer, MD, MPH, Rogerio A. Lobo, MD, and James A. Simon, MD, CCD, NCMP, FACOG, discuss issues in HT, including counseling and managing patients who are concerned about the safety of HT, resolving progestogen-related side effects, and long-term use of HT, quality of life, and statins. They also provide insights for developing treatment plans tailored to the individual patient. Read the complete CME information
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Release date: August 5, 2009
Expiration date: August 5, 2010
For more information on this topic, read the first newsletter in this series. Case:The patient is 54 years old and is about 3 years postmenopausal. She began using hormone therapy (HT) (conjugated equine estrogen [CEE], 0.3 mg/medroxyprogesterone acetate [MPA], 1.5 mg/d) about 15 months ago. She had tried to “gut it out” for about 1½ years because she had heard horror stories about the risks of this therapy, but finally her vasomotor symptoms got the best of her and, at the suggestion of her gynecologist, she began this treatment regimen. She has recently relocated and has had several health care providers over the past few years. She has been pleased with her quality of life. She has been compliant with therapy for the past 15 months; however, now that her vasomotor symptoms have abated and she is sleeping well at night, she realizes that she is still bothered by other symptoms and wonders if these are due to her “progesterone.” These symptoms include unpredictable vaginal bleeding and breast tenderness. These and other common progestogen-related side effects occur in approximately 35% of HT users and often result in discontinuation of therapy. Usually, they occur within the first 6 months of treatment, but symptoms can develop, may change, or the patient may recognize them over time. Few studies quantify actual effects, particularly in head-to-head studies of agents, or provide practical information for clinicians.1 Clinical goals: For this patient, the goal should be to reestablish a regimen that alleviates vasomotor symptoms, provides endometrial protection, and minimizes progestogen-related side effects. Because her symptoms and her underlying metabolic state may change over time, adjustments to a patient’s HT regimen should be considered at each annual checkup, or sooner if she is uncomfortable. Several strategies are available, including changing the dosage, route of administration, or type of progestogen used. In evaluating appropriate options for this patient, the key take-home message for clinicians is that progestogens vary in their formulation, bioavailability (and therefore potency), and effects.1,2 As noted earlier, periodic review of each patient’s status should be conducted at least annually, including a discussion of progestogen- and estrogen-related side effects that may develop over time. When these occur, a variety of strategies may be used to change her regimen. More than one strategy may be used, but only one should be tried at a time. The goal is to improve tolerability and maintain compliance. Select an agent that may provide a better symptom profile. Individual responses to particular progestogens may occur; these responses may not relate to the populations of women studied and cannot be predicted. Limited data have shown that improvement in side effects may be resolved by switching among available progestogens. In general, if a patient has side effects with a progestogen in one category (see Figure 1) changing to a progestogen in a different category makes more sense than changing to an alternative progestogen within the same category. The patient’s individual risks for diabetes, dyslipidemia, thrombosis, and breast cancer should be evaluated carefully. Discussion should include such details as whether she ever had a pregnancy-related deep vein thrombosis (DVT) or has a family history of clotting disorders, which may suggest an uncommon prothrombotic mutation that may elevate risk associated with oral HT. FIGURE 1. Classification of exogenous progestogens 
LNG, levonorgestrel; MP, micronized progesterone; MPA, medroxyprogesterone acetate; NETA, norethindrone acetate. In one investigation,3 switching from MPA to micronized progesterone (MP), in women whose symptoms were similar to this patient’s, provided an improvement in all somatic, vasomotor, and psychological symptoms (by 32%, 50%, and 45%, respectively) (Figure 2).3 Patients also noted improvements in the areas of cognitive difficulties, sexual functioning, sleep disturbances, vaginal bleeding, and anxiety. This report underscores the variability of progestogenic effects in individual patients. It is, therefore, of great relevance to this patient since, other than the bothersome progesterone side effects, she is comfortable with orally administered HT. FIGURE 2. Estradiol + MPA or MP for HT: Effect on quality of life 
HT, hormone therapy; MP, micronized progesterone; MPA, medroxyprogesterone acetate. *P < .001 vs MP. Reprinted with permission from Fitzpatrick LA, et al. J Womens Health Gend Based Med. 2000;9:381-387. The most commonly used US Food and Drug Administration (FDA)-approved progestogens for HT are MPA, MP, norethindrone acetate (NETA), and drospirenone (DRSP). Clinicians should be attentive to the differences among these agents. Although progestogens are structurally related (Figure 1), animal and basic studies suggest that androgenic effects are associated with NETA and levonorgestrel, and antiandrogenic effects with MP and DRSP. Antimineralocorticoid effects occur with MP and DRSP.1 Sedative effects occur with oral MP because a metabolite, allopregnanolone, which increases after oral administration, interacts with the gamma-aminobutyric acid (GABA) receptor complex in a manner similar to benzodiazepines. This results in a sedative effect that typically lasts between 2 and 6 hours.4 In animal studies, the anxiolytic actions of progesterone have been shown to reduce measures of anxiety.5 Because of this sedative effect, MP should be administered at bedtime. Bloating and breast tenderness: Significant patient variability Progesterone and spironolactone have antimineralocorticoid (or diuretic) effects, which benefits women who experience progestin-related bloating. However, some patients metabolize progesterone more strongly to 11-deoxycorticosterone, which may result in breast tenderness, edema, and mood changes.6,7 Breast tenderness is most common in the first several months of a new HT regimen and is frequently also related to an increase in estrogenic stimulation of glandular development together with progestogen-mediated secondary effects. Most, but not all, women adjust to new effective levels after several months. The differing effects observed in some patients are important. In our clinical practice, we note significant patient-to-patient variability in breast tenderness and bloating. Although there are no studies to address this variability, it is our experience that this profile may be more commonly associated with administration of MPA. Reducing the dose of estrogen may also help in this situation. Bleeding patterns and progestogens Since this patient has been on HT for more than a year and has not—until recently—experienced breakthrough bleeding or spotting, it is important to rule out neoplasia or endometrial cancer by endometrial sampling. Transvaginal ultrasound is not always effective for this purpose.8 Assuming no disease is present, efforts should focus on eliminating breakthrough bleeding, as bleeding patterns and breast symptoms are prominent in women’s decisions to discontinue therapy. In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, women recorded bleeding patterns and other side effects in a daily diary. Excess bleeding was defined as any bleeding other than that associated with a usual cycle for women using cyclical HT regimens, or any bleeding for women on placebo or continuous HT regimens. The results are shown in Figure 3.9 FIGURE 3. PEPI trial: Episodes of excess bleeding* 
CEE, conjugated equine estrogens; MP, micronized progesterone; MPA, medroxyprogesterone acetate. Treatment regimens: CEE: 0.625 mg/d
CEE + continuous MPA: CEE 0.625 mg/d + MPA 2.5 mg/d
CEE + cyclical MPA: CEE 0.625 mg/d + MPA 10 mg/d for 12 d/mo
CEE + cyclical MP: CEE 0.625 mg/d + MP 200 mg/d for 12 d/mo *Excess bleeding was defined as any bleeding in the groups receiving placebo, CEE, and CEE + continuous MPA, and >6 episodes within the 6-month interval in the groups receiving CEE + cyclical MPA and CEE + cyclical MP. Reprinted with permission from Lindenfeld EA, Langer RD. Obstet Gynecol. 2002;100(5 pt 1):853-863. PEPI showed that, in the first 6 months of usage, cyclical or continuous MPA with CEE was associated with significantly more days of bleeding than was cyclical MP/CEE. Thereafter, continuous MPA was associated with less bleeding, although unexpected breakthrough bleeding remained relatively common with that continuous regimen. Comparing the 2 cyclical regimens, MP/CEE was associated with fewer days of bleeding than was MPA/CEE throughout the 3-year study. Quantity of bleeding also varied, such that MP/CEE was associated with significantly fewer pads used than MPA/CEE. Over 3 years’ usage, bleeding duration was lowest when CEE was used with continuous MPA, followed by MP, and then by cyclic MPA. The number of unanticipated bleeding episodes with MP was similar to that of placebo. However, cyclical MPA was associated with 2 times and continuous MPA with 9 times more unanticipated bleeding episodes than MP (see Figure 3).9 A comparison of bleeding patterns of CEE/MPA and ethinyl estradiol/NETA also demonstrated more breakthrough bleeding with MPA, although both progestogens produced more initial breakthrough bleeding than was seen with placebo (Figure 4).10 FIGURE 4. Bleeding associated with HT regimens using MPA or NETA 
CEE, conjugated equine estrogens; EE, ethinyl estradiol; MPA, medroxyprogesterone acetate; NETA, norethindrone acetate. Reprinted from Am J Obstet Gynecol, Vol 188, No 1, Simon JA, et al, Reduced vaginal bleeding in postmenopausal women who receive combined norethindrone acetate and low-dose ethinyl estradiol therapy versus combined conjugated equine estrogens and medroxyprogesterone acetate therapy, p 92-99, Copyright 2003, with permission from Elsevier. Since the only purpose of a progestogen is to protect against endometrial hyperplasia, the dose of progestogen required is related to the dose of estrogen. In general, lower-dose HT regimens are associated with lower rates of spotting and breakthrough bleeding, while rates of amenorrhea increase.1 However, this introduces the potential for a return of vasomotor symptoms. According to a panel convened by the National Institutes of Health, low-dose estrogen can be defined as ≤0.3 mg/d of conjugated equine estrogen, ≤0.5 mg/d of oral micronized estradiol, ≤25 mcg/d of transdermal estradiol, or ≤2.5 mcg/d of ethinyl estradiol. However, the panel could not recommend the lowest dose and shortest duration for effective relief of menopausal symptoms, based on available evidence.11 A summary of low-dose regimens based on these thresholds appears in the Table. TABLE. Low-dose hormone therapy for postmenopausal symptoms VVA, vulvar-vaginal atrophy. aAlso available in normal-strength formulations, which may have additional indications. bIndications refer to moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar/vaginal atrophy, both in association with menopause. cWomen with a uterus who are prescribed estrogen-only agents should also take a progestin to decrease their risk of endometrial cancer. dAlso available as a generic, with the same dosages and indications as the brand name drugs. eAt 25 mcg dose, used only for prevention of osteoporosis from menopause. Source: Facts & Comparisons online. www.factsandcomparisons.com Accessed May 28, 2009; Manufacturers’ prescribing information. However, many clinicians consider the threshold for low-dose options to be somewhat higher, at 0.625 mg/d of conjugated equine estrogen (eg, Enjuvia, 0.45 mg conjugated estrogens), <0.75 md/d of oral micronized estradiol, and <50 mcg/d of transdermal estradiol. Vaginal delivery of progesterone in gel or capsule form is not FDA approved for endometrial protection in postmenopausal HT. This strategy is attractive to maximize desired local effects and minimizes the potential for first-pass systemic side effects associated with oral administration. Alternate-day dosing may be appropriate. However, in addition to the current lack of FDA-approved products for this approach, clinical experience suggests that patients may not be compliant with nonoral delivery. Some clinicians have become interested in the off-label use of the levonorgestrel intrauterine device for HT. The available dosage in the United States is approved as a progestin-only contraceptive, and is higher than that typically used for HT. A lower-dose version that might be more appropriate for use in postmenopausal women is being developed for this indication, yet unapproved in the United States as of the publication of this newsletter. This has created some confusion among US practitioners. Clinicians should keep in mind that this formulation is useful for women who experience dysfunctional bleeding but may not be a solution for patients who are progestogen intolerant. In addition, the difficulty of placing such a large device may significantly limit its use among many postmenopausal women, particularly those who are nulliparous. For most patients, the strategies described above will be effective. However, some patients may continue to be progestin intolerant. Long-cycle estrogen plus progestogen administration reduces the number of times that a patient is exposed to progestogens by extending the time between doses. These regimens typically include daily estrogen (eg, 0.625 mg/d CEE) plus progestogen (eg, 10 mg/d MPA) for 10 to 14 days every 3 to 4 months; in fact, every 2 months is an option for some women. This should vary by patient age and may NOT be safe in women within 5 to 10 years of menopause.12,13 In the Scandinavian Long Cycle Study, patients received 17beta-estradiol (2 mg/d, twice the standard dosage) with 10 days of progestin (NETA, 1 mg/d), either every 4 weeks or every 12 weeks. Patients in the 12-week, long-cycle group had a significantly higher incidence of endometrial hyperplastic changes (P = .003) as well as more irregular bleeding than did those in the monthly group. Similarly, a Cochrane review of 30 trials found a higher incidence of endometrial hyperplasia among women receiving long-cycle estrogen plus progestogen than among those receiving a monthly regimen.14 Sparse data on endometrial safety is an issue.12,13 In our experience, long-cycle regimens are rarely indicated in the early years of menopause because of the high risk of hyperplasia. It is more useful in older patients who may choose to remain on HT. Careful patient monitoring will be required. This strategy requires close monitoring of patients for endometrial hyperplasia. Following initial evaluation with endometrial biopsy to rule out disease,8 evaluation by transvaginal ultrasound at 6- to 12-month intervals, or immediately when bleeding occurs, is essential for endometrial safety CONCLUSION Patients such as this, who wish to achieve the benefits associated with HT use without its undesirable progestogen side effects, will need close collaboration and good communication with their prescribing clinician. Goals should focus on achieving compliance; amelioration of side effects will play an important role in this process. 1. Lobo R. The progestogen primer. Presented at: 19th Annual Meeting of the North American Menopause Society; September 24-27, 2008; Orlando, FL. http://www.proxy-host.com/NAMS/presentation_6.html. Accessed April 27, 2009. 2. Archer D. Tailoring progestogen therapy to the individual. Presented at: 19th Annual Meeting of the North American Menopause Society; September 24-27, 2008; Orlando, FL. http://www.proxy-host.com/NAMS/presentation_6.html. Accessed April 27, 2009. 3. Fitzpatrick LA, Pace C, Wiita B. Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey. J Womens Health Gend Based Med. 2000;9:381-387. 4. Arafat ES, Hargrove JT, Maxson WS, et al. Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites. Am J Obstet Gynecol. 1988;159:1203-1209. 5. Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J Neuroendocrinol. 1995;7:171-177. 6. Sitruk-Ware R, Bricaire C, de Lignieres B, et al. Oral micronized progesterone. Bioavailability, pharmacokinetics, pharmacological and therapeutic options—a review. Contraception. 1987;36:373-402. 7. Andréen L, Sundström-Poromaa I, Bixo M, et al. Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone. Psychoneuroendocrinology. 2005;30:212-224. 8. Langer RD, Pierce JJ, O’Hanlan KA, et al. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. N Engl J Med. 1997;337:1792-1798. 9. Lindenfeld EA, Langer RD. Bleeding patterns of the hormone replacement therapies in the postmenopausal estrogen and progestin interventions trial. Obstet Gynecol. 2002;100:853-863. 10. Simon JA, Liu JH, Speroff L, et al. Reduced vaginal bleeding in postmenopausal women who receive combined norethindrone acetate and low-dose ethinyl estradiol therapy versus combined conjugated equine estrogens and medroxyprogesterone acetate therapy. Am J Obstet Gynecol. 2003;188:92-99. 11. NIH State-of-the-Science Panel. National Institutes of Health State-of-the-Science Conference statement: management of menopause-related symptoms. Ann Intern Med. 2005;142:1003-1013. 12. North American Menopause Society. Role of progestogen in hormone therapy for postmenopausal women: position statement of The North American Menopause Society. Menopause. 2003;10:113-132. 13. Bjarnason K, Cerin A, Lindgren R, et al. Adverse endometrial effects during long cycle hormone replacement therapy. Scandinavian Long Cycle Study Group. Maturitas. 1999.16;32:161-170. 14. Lethaby A, Suckling J, Barlow, et al. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev. 2004;(3):CD000402. Click here to take the free CME/CE test online OBG Management ©2009 Quadrant HealthCom Inc. | 
