1°Care Exchange

From Speroff et al.(1994). Clinical Gynecological Endocrinology and Infertility. Baltimore: Williams & Wilkins, pg. 583.

*From Hoyert DL et al. Deaths: final data for 1997. National Vital Statistics Reports 47 (19), June 30, 1999.

2. What estrogen preparation is the best?

• Conjugated equine estrogen (CEEs) (Premarin) is the estrogen most commonly used in the United States and the most intensively studied.

• CEEs are made from pregnant mares’ urine; some patients have concerns about animal cruelty due to collection methods.

• Other oral forms are made from synthetically manipulated plant estrogens. CEE equivalent doses are seen in Tables 3 and 4 (page 3).

• Transdermal estradiol avoids hepatic metabolism; good for patients with high triglycerides. However, patients may benefit from the favorable lipid changes caused by the intrahepatic metabolism of oral estrogen.

• Injected estrogen causes wide fluctuations in blood levels. Potentially beneficial lipid changes do not occur with injected estrogen.

• Intravaginal estrogen can be used as an adjunct to treat urogenital atrophy. However, absorption is erratic. Long-term use is not recommended.

Table 4. Acceptable regimens for HRT in women with a uterus

Compound	Example	Advantages	Disadvantages
Estrogen QD* + continuous low dose progestin]	Premarin 0.625 mg + Provera 2.5 mg	80% of women amenorrheic by 1st year	Bleeding tends to be irregular
Estrogen QD + intermittent Progestin**	Premarin 0.625 daily + Provera 10 mg d 1-13	Bleeding predictable, occurs about d 9 of progestin. Best studied	Amenorrhea does not usually occur although bleeding gets lighter over time
Estrogen QD + lower dose, intermittent progestin	Premarin 0.625 + Provera 5 mg d 1-13	Fewer side effects, breast tenderness, depression	Risk of endometrial hyperplasia probably greater than standard dose
Estrogen QD + levonogestrel IUD	Premarin 0.625 + IUD	No progestin side effects Amenorrhea by 6 mos IUD good for approx 18 mos.	Levonogestrel IUD not available in the U.S.; no studies published using progestasert (should work equally well). Some women do not tolerate insertion or presence of IUD. Irregular bleeding at onset
Estrogen QD + natural Progesterone cream	Premarin 0.6235 + Crinone 90 mg d 17, 19, 21, 23, 25, 27 of cycle	Fewer progestin side effects than oral	More expensive; may be difficult to remember for some women
Estrogen QD + progestin X 2 wks q 3 mos.	Premarin 0.625 + Provera 10 mgs 14d q 3 mos	Fewer episodes of progestin side effects. Q3 mo menses	No studies documenting efficacy of prevention of endometrial hyperplasia Possibly increased risk of uterine CA
Estrogen QD + Depo Provera 150 mg IM q 3 mos	Premarin 0.625 + DepoProvera 150 mgs IM	Amenorrhea	Depo Provera side effects include Weight gain Depression
Combipatch	Single device with estrogen and progesterone	Does not adversely impact lipids.	More studies needed.

* Equivalent estrogen doses: Premarin 0.625 po; Ortho-Est .625 po; Nevest 0.625 po; Ogen 0.625 po; Estrace 1 mg po; Estinyl 0.05 mg; Estraderm 0.05 mg biw; Alera 0.05 biw; Fempatch 0.05 biw; Climera 0.05 qw.

] Equivalent low dose progestins: Provera (MPA) 2.5 mgs qd; Norethindrone .035 mg qd; Aygestin 2.5 mg qd.

** Equivalent intermittent progestin doses; Provera 10m; Aygestin 5 or 10 mg; Micronor 0.07

3. Should estrogen be given cyclically (25 days per month?)

4. Is there any way to evaluate adequacy of estrogen dosing?

5. When should HRT be started?

• At or soon after menopause. However, bone and heart benefits have been documented in women who begin estrogen up to age 74.

• Women with decreased bone mass achieve greatest gains in bone mass with estrogen + calcium (1000-1500 mg/day) + vitamin D (400-800 IU/day).

6. How long should estrogen therapy continue?

• If relief of vasomotor symptoms is the only goal, 5 years or less will be needed.

• If prevention of cardiac disease or osteoporotic fractures is desired, treatment must be lifelong.

7. Does taking estrogen increase the risk of breast cancer?

• Use of estrogens >5 years has been associated with increased risk of breast cancer in most studies.

• Addition of progestins does not decrease the risk.

• The Iowa Women’s Health Study found that the additional breast cancers associated with HRT tended to be a less malignant with fewer metastases and lower morbidity rates (Gapspur et al. JAMA 281(22): 2091-7, 1999).

• For most women, except those at high risk of breast cancer (2 first degree relatives) and very low risk for osteoporosis and heart disease, long-term estrogen use decreases overall mortality (Col et al. Arch Int Med 159:1458-66, 1999).

8. Should women with established heart disease be started on estrogen?

Conclusion: in older women with heart disease, initiate other prevention measures first (ASA, lipid lowering, HTN control, smoking cessation) then add HRT (Hulley et al. JAMA 280(7):605-13, 1998).

9. What is the Estring?

• Pessary-like ring which gives off tiny amounts of estrogen over a 3 month period.

• Used to treat atrophic vaginitis.

• Can be removed for cleaning. Vaginal odor is a bothersome side effect.

• Very minimal systemic absorption so no bone protection or heart disease prevention. No need to oppose with progestins.

10. What are the contradictions to estrogen use?

• Unexplained vaginal bleeding.

• Thromboembolic disease related to estrogen use.

• Active liver disease.

• Known or suspected breast cancer or endometrial cancer.

 

11. Can women with previous breast or endometrial cancer take HRT?

• Women who have gone 5 years past treatment for endometrial cancer and are cancer-free can probably safely use HRT.

• Some women with no current or recent evidence for breast cancer may decide to take HRT under close supervision. Consider using a SERM (see 12. below).

12. What are the plusses and minuses of SERMS

• SERMS -- Selective Estrogen Receptor Modulators.

• Act as agonists or antagonists in specific tissues.

• Raloxifene (Evista™) increases bone density to the same degree as estrogen but with half the effect on lipids and very little stimulation of the breasts and endometrium.

• 70% decreased risk of invasive breast cancer.

• Do not decrease hot flashes; may increase them.

13. Can birth control pills (BCP) be used for HRT?

14. Who needs to use progestational agents?

• All women with an intact uterus and women with a history of endometriosis should use a progestin to prevent development of endometrial hyperplasia.

• Women with hysterectomy and no previous history of endometriosis do not need progestins.

 

• Medroxyprogesterone acetate (MPA) (Provera™) is most commonly used in the United States.

• MPA partially counteracts cardiac and lipid benefits of estrogen.

• Norethindrone acetate (Aygestin) is the progestin most often used in Europe.

• Norethindrone or norethindrone acetate may be tolerated when MPA is not.

• Continuous low dose progestin (MPA 2.5, Norethindrone 0.035) causes light irregular bleeding which stops by 1 year in 80% of women.

• Higher dose intermittent (MPA 10 mg, Norethindrone 0.07) is given for 12-14 days per month. Women generally begin spotting on day 9 and continue for 5-6 days.

• Progesterone IUDs result in endometrial atrophy; often tolerated when oral progestin is not.

• Oral natural progesterone is not well tolerated primarily due to somnolence.

• Intravaginal natural progesterone (Crinone 8%) applied qod from days 15-27 has minimal systemic side effects and excellent prevention of endometrial hyperplasia.

Table 6. Progestins used for postmenopausal therapy

16. Are there other alternatives for women who do not tolerate Progestins?

• MPA 5 mg for 12-14 d/mo is often used. There are no published studies that demonstrate the relative safety of this lower dose of MPA.

• Hysterectomy may be an option for women who cannot tolerate any progestin.

17. When should androgens be added?

• Women whose vasomotor symptoms are not controlled using equivalent of CEE 1.25 may need androgen..

• Women on HRT with low libido.

18. What dose of androgen is appropriate?

• Androgen-estrogen combinations are available. Estratest has esterified estrogen with methyltestosterone 0.625mg/1.25mg or 0.625mg/2.5mg.

• 1/3rd of women treated with these low doses of testosterone will develop hirsuitism or acne

• Higher male-level androgens are associated with side effects of clitoromegaly, voice deepening, skin problems and worsening lipid profiles.

• Addition of testosterone diminishes positive effects of estrogen on serum lipids.

• Testosterone patches would alleviate adverse lipid changes of oral testosterone, but doses available are too high for use in women.

19. Can women use food products to treat hot flashes and prevent osteoporosis?

• Phytoestrogens (also called isoflavones) are contained in soy products and legumes (Table 7).

• Recent studies in animal models suggest that a component of soy protein, most likely isoflavones, reduces vasomotor events.

• Results from 1 clinical trial showing that phytoestrogens reduce hot flashes and maintain bone density were presented but have not been published in the peer reviewed literature (Messina M. Soy as a possible alternative to hormond replacement therapy. Presented at Soy Foods Symposium, Lexington, KY, 1997).

• Ipriflavone (a synthetic isoflavone dietary supplement) (600 mg/day) has been shown in clinical trials to maintain bone density and to be well-tolerated with few side effects (Setchell KDR and Cassidy A J Nutr 129:758S, 1999).

• Soy products are a good source of calcium, which is also essential for bone health.

20. Is there any evidence that herbal medicines, such as ginseng and black cohosh, provide relief from menopausal symptoms?

Few placebo-controlled clinical trials have been published validating the use of various alternative therapies for relief of menopausal symptoms. Table 8 (below) shows the most often used alternative therapies and the evidence for their use.

Adapted from: Reinli K and Block G. Phytoestrogen content of foods-A compendium of literature values. Nutr Cancer 1996;26:123-148.

 

21. Is DHEA safe and effective to prevent/ postpone aging?

• DHEA levels decline with increasing age.

• Published evidence that DHEA is beneficial is equivocal.

• Some studies suggest it may be effective in treating depression, erectile dysfunction, memory loss and obesity but studies were too small to be conclusive.

• Risk of liver damage. Because metabolism varies with each individual, estrogen or testosterone excess may result leading to side effects.

 

Each quarter, this new section of 1° Care Exchange will feature answers to questions from practitioners. In this issue, we report answers to specific questions raised about Rocky Mountain Spotted Fever. The answers come from a variety of sources and have been critically evaluated by faculty and residents in the Department of Family & Preventive Medicine as part of our monthly Journal Club.

1. How should children less than 8 years of age with suspected Rocky Mountain Spotted Fever (RMSF) be managed?
   Doxycycline is the antibiotic agent of choice even for children. Given the rapid progression of the disease and the high mortality in untreated individuals, children with suspected RMSF (risk factors include flu-like symptoms in summer and exposure to ticks) should be treated empirically. Teeth staining, which can be a problem with tetracyclines, is very unlikely with a single 10-day course of doxycycline.
2. How should pregnant patients with suspected RMSF be managed?
   Pregnant women with risk factors for RMSF (above) should be hospitalized and started on a course of chloramphenicol, IV x 5 days, pending laboratory confirmation. Doxycycline is not recommended because it can cause hepatic problems in women and stains developing teeth in infants.
3. What symptoms or signs should prompt admission to the hospital of patients with RMSF?
   Pregnant women should be hospitalized immediately and started on IV chloramphenicol.. No specific guidelines or studies have reported criteria for hospitalization for RMSF but patients with RMSF can become hypotensive and critically ill very quickly. Patients with suspected RMSF should be monitored and admitted according to severity of symptoms or development of complications.
4. What is the best way to remove a tick that has embedded in a patient’s skin? Removing the tick early can be an important preventive measure in RMSF. The tick must be attached for 6-24 hours before it infects its victim. Regular inspection of the body following exposure and rapid removal of ticks can prevent disease.

ACKNOWLEDGMENT: Special thanks to Meg Moore, R.Ph., director of the Family Medicine Pharmacy, for her help with the dosage and cost information contained in this issue.

If you have clinical questions you would like us to investigate, or if you would like additional information about the 1° Care Exchange, please contact Laine McCarthy, editor-in-chief, by e-mail (laine-mccarthy@ ouhsc.edu) or by phone (405) 271-2374.

1°Care Exchange