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Insomnia in Women: Menopause and Melatonin
Part III of III-Part Series
By Susan T. Marcolina, MD, FACP, and Beth Rosenshein, BSEE. Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA; Beth has her BA in Electrical Engineering; both report non financial relationships relevant to this field of study.
When vasomotor events (vme) occur as a consequence of estrogen withdrawal, they respond to estrogen replacement.1 Several randomized, placebo-controlled trials indicate that estrogen replacement significantly relieves hot flashes compared to placebo2-4 and to other botanical interventions.5 At the present time, however, the recommended treatment for moderate-to-severe VMEs is the lowest effective dose of hormone therapy for the shortest duration.6 It is not universally understood what ovarian hormone replacement is and what the recommendations should be for women who continue to have long-term problems with VMEs and, by proxy, insomnia; therefore, consideration must be given to the option of long-term physiologic ovarian hormone replacement therapy.
Hormone Replacement Therapy and the Women's Health Initiative
Current recommendations regarding hormone replacement therapy come from the findings of the Women's Health Initiative, a prospective, randomized, controlled trial of hormone therapy involving more than 26,000 postmenopausal women (average age, 63 years), 10,739 of whom had a hysterectomy and were, therefore, randomized to CEE or placebo and 16,608 with a uterus who were randomized to CEE plus MPA or placebo. The arm of the trial assigned to the CEE plus MPA was terminated in 2002 due to an excess number of women with venous thromboembolism (VTE), coronary heart disease, stroke, breast cancer, and total mortality.7 Subsequent secondary analyses of these findings and further recent clinical studies have uncovered several important factors to consider about hormone replacement therapy. Rousseau and colleagues concluded that there was a tendency, though statistically not a significant one, toward reduced CHD risk in younger subset of women (50-59 age group) beginning the replacement therapy closer to onset of menopause compared to those starting the hormone replacement therapy more than 10 years after climacteric onset.8 This suggests a window of time for initiating hormone replacement wherein it may play a role in decreasing risk for CHD. It is important to keep in mind that the WHI was designed as a primary prevention trial and not as a symptom treatment trial. The results obtained in this trial were based upon the use of oral Premarin (CEE or conjugated equine estrogens) and Provera and, as such, may not be generalizable to different populations of women using different HRT formulations via different administration routes. CEEs are a complex mixture of at least 9 different estrogens, most of which are present only in horses.9
Since the WHI, the Estrogen and Thromboembolism Risk (ESTHER) study has shown that the route by which hormone therapy is administered, and the type of hormone replacement therapy used, can further attenuate the risks identified by the WHI. Scarabin and colleagues in a prospective, case-controlled trial, have shown that the odds ratio for VTE in current users of oral estrogen replacement therapy were 3.5 compared to .9 in current users of transdermal ERT. Most of the study subjects on transdermal estrogen used transdermal 17 beta estradiol, identical to the 17 beta estradiol produced by the functional ovary. Avoidance of the first pass effect of the liver with transdermal administration of hormones avoids the hepatic elaboration of prothrombotic species, such as prothrombin factors 1 and 2 and proinflammatory factors such as C-reactive protein (CRP) that is seen with oral estrogen therapy.10,11 An elevation in CRP is an independent risk factor for coronary artery disease.12,13
Another important consideration in replacement therapy is the option for progesterone replacement. All women with a uterus must take a progestational agent if prescribed estrogen replacement for VMEs to prevent the risk of endometrial cancer associated with continuous unopposed estrogen.14 The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, a placebo-controlled, double-blinded study with a 3-year follow-up examined the effects of different progestogens on 875 women (45-64 years of age) randomized to 5 treatment regimens: 1) placebo, 2) oral conjugated equine estrogen (CEE) .625 daily, 3) oral CEE plus Provera (medroxyprogesterone acetate) (MPA), 10 mgs days 1-12 of the month, 4) oral CEE plus MPA 2.5 mgs daily, and 5) oral CEE plus micronized progesterone (MP) 200 mgs days 1-12. All treatment groups had lower (LDL) low density lipoprotein levels, higher HDL levels (the CEE only and CEE plus MP regimen more than CEE plus MPA regimen), and higher triglyceride levels than placebo. The cyclic MP had the most favorable effect on HDL-C and LDL-C, preserving the effects of the CEE without risk of endometrial hyperplasia.15
Androgens in Ovarian Hormone Replacement Therapy
Heretofore, androgens have not been included as “hormone replacement therapy” despite the fact that women's bodies make approximately 71% of the androgens elaborated by men, one third of which are from ovarian sources with the other two thirds elaborated in the body's adipose stores and adrenal glands.16 Standard hormone replacement has included estrogen and progestins in the oral forms and such routes of administration further reduce endogenous androgenic activity because oral estrogens both suppress gonadotropins, leading to reduced ovarian androgenesis and increase sex hormone-binding globulin (SHBG), which in turn diminishes bioavailability of androgens.17 Animal studies have shown that testosterone protects breast tissues due to its effects on the two types of estrogen receptors, ER beta and ER alpha. The ratio of these two receptors plays an important role in breast cancer. Whereas estradiol increases ER alpha; testosterone decreases ER alpha, and increases ER beta. Prior to the onset of ovarian failure, ER beta is expressed to a greater extent than ER alpha, and this is reversed after ovarian failure due to the declining androgen levels. This decline in ovarian androgen production actually precedes the climacteric by approximately 10 years.18-20 NIH-sponsored primate studies in 200021 and 200319 designed to investigate the effects of testosterone on the breast cancer gene MYC (implicated as a mediator of estrogenic tumorigenesis in the breast), and breast epithelial cell proliferation showed that androgen addition to estrogen treatment reduced mammary epithelial cell MYC expression. Testosterone treatment also reduced ER alpha and increased ER beta expression in estrogen-treated monkeys and, thus, had a protective effect on the estrogen-treated breast in the same way that progesterone has the protective effect of preventing hyperplasia in the estrogen-treated uterus. Their overall conclusion was that physiological estrogen/androgen hormone replacement might be beneficial to women and girls with ovarian failure.22
Hofling and colleagues demonstrated in a prospective, randomized, double-blind, placebo-controlled study of 99 postmenopausal women on continuous combined oral estradiol 17 beta and norethisterone acetate demonstrated that those who received a testosterone patch (Intrinsa Patch 300 micrograms testosterone /24 hours applied twice weekly) had no significant increase in breast cell proliferation form baseline through the 6-month study period. In contrast, the group treated with the oral estrogen/progestin and the placebo patch had more than a five-fold increase (P greater than .001) in total breast cell proliferation from baseline to 6 months. The tissue proliferation indices in this study were quantified from immunocytochemical staining of breast biopsies obtained by fine needle aspiration (FNA) taken before and after hormone therapy treatment. The information from this study is important because it provides a means by which to mitigate the increased risk of breast cancer seen with combined estrogen/progestogen therapy in randomized, controlled trials such as the WHI.23
There has been thoughtful concern that hormone therapy should be initiated for ovarian failure, and a discussion about what such treatment would involve.24 With this in mind, all of the ovarian hormones, estrogen, progesterone, and testosterone, should be included in a hormone replacement regimen, and efforts should made to bring ovarian hormone replacement therapy into line with replacement therapy given for other hormone deficiency syndromes, such as insulin dependent diabetes, hypothyroidism, and growth hormone deficiency, where physiologic hormone replacement is the standard of practice.
Physiologic Hormone Products and Dosages for Postmenopausal Women
Since natural progesterone in powdered form is poorly absorbed via the oral route, due to gastric acid destruction, it must be micronized into smaller particles and dissolved in oils consisting of long-chain fatty acids, primarily peanut oil. The micronized progesterone is identical in chemical structure to endogenous progesterone, and is manufactured from the wild yam or soybean precursor diosgenin. It is available as Prometrium or through compounding pharmacists as oral micronized progesterone (MP).25,26 The FDA recognizes a dose of 200 mgs for 12 sequential days per month for the prevention of endometrial hyperplasia in women taking estrogen replacement therapy.27 Progesterone powder can be compounded, by a compounding pharmacy in a cream base, and applied topically. Generally, 60-100 mgs of progesterone is suspended per gram of cream (giving a 6-10% w/v suspension), which can be dispensed in syringes for ease of application. The dosage can be adjusted to achieve blood levels of 12,000-25,000 pg/mL, which is the average progesterone range over the course of the menstrual cycle. After one year, an endometrial biopsy should be done to assess progesterone effect, with subsequent biopsies yearly depending upon symptoms.
Several transdermal delivery systems for estradiol are available in the United States. Estradiol is released from an alcohol gel reservoir or directly from the adhesive matrix of a transdermally applied patch. Table 1 provides examples of the available transdermal estradiol preparations. The most commonly used dosages are .05 and .1 mg patches, which are applied to the skin once to twice weekly depending upon the product.
The patches are designed to release .014-.1 mg of estradiol daily for 3.5-7 days. Menostar supplies the lowest dose of estrogen for prevention of osteoporosis. A patch is applied to the clean, dry, lotionless area of skin on the abdomen or buttock one or twice per week. The 7-day adhesive matrix patch produces similar mean estradiol levels to the 3.5 day patch, but with less variation in estradiol levels. The .1 mg estradiol patch can raise the serum level of estradiol from 17-195 pg/mL, which is a wide range not influenced by weight. Target blood levels of estradiol for replacement are 50-150 pg/mL, which is generally the average level measured during the course of the menstrual cycle. Since it takes only a day to reach a steady state level due to the short half-life of estradiol, a blood level of estradiol, two days after applying the patch, indicates how well the estradiol is absorbed transdermally. Dosages can be adjusted to keep the target blood levels in range.29
Intrinsa is a transdermal testosterone matrix patch, specifically developed for use in women with surgical menopause suffering from Hypoactive Sexual Desire Disorder (HSDD). Each patch contains 8.4 mgs of testosterone, and releases 300 m over a 24-hour period of time. After patch application, average total testosterone levels are raised from 17 to an average of 79 ng/dL on the twice weekly Intrinsa patch. It can be obtained by ordering from www.atlanticdrugs.com, a company located in the United Kingdom. It is not currently FDA approved for use in the United States.30 Patients on CEE (Premarin) should not use Intrinsa.31
Oral micronized progesterone or Prometrium is the only FDA-approved progesterone product available and, because it contains peanut oil, its use should be avoided in persons with nut allergies. It can also be sedating and, therefore, should be taken just prior to bedtime. If taken with food, absorption is increased, which can intensify its sedative side effects. Symptoms of bloating and breast tenderness are dose related.27,32 For persons with peanut allergies or oral intolerance, transdermal preparations of progesterone can be formulated by compounding pharmacists with dosage guided by hormone blood levels and endometrial biopsies to assess the balance of secretory and proliferative effects on the endometrium. A major concern with progesterone creams is that serum progesterone levels achieved with the creams are too low to have an effect on the endometrium; however, antiproliferative effects on the endometrium have been demonstrated even when circulating levels of progesterone are low. The status of the endometrium should be evaluated with an endometrial biopsy within a year of initiating hormone therapy. In its guidelines to the pharmaceutical industry, the US FDA recommends endometrial biopsies at the beginning and the end of an HRT trial.33 Sonography of the uterus can provide additional useful information regarding endometrial thickness (should be less than 5 mm in postmenopausal women) and the presence of polyps or fibroids. Abnormalities identified either sonographically or by endometrial biopsy should be more completely assessed with a gynecologic referral.
Intrinsa is expensive at $16-$20/patch. The patch can cause mild erythema, inflammation, and itching at the site, which can be relieved by rotation of patch sites. Side effects of acne and hirsutism can be seen with supraphysiologic dosages, but are uncommon with the physiologic dosage provided by this patch.34
The use of estradiol patches is associated with mild skin erythema, itching, and irritation, which can be mitigated by frequent rotation of patch sites. Mild breast tenderness and irregular vaginal bleeding can be side effects, as with oral estrogen, but both symptoms can be attenuated by dosage adjustment.35 If vaginal bleeding remains persistent, further evaluation is necessary.
Given the unique factors that contribute to insomnia in women with ovarian failure, including VMEs, sleep disordered breathing, and decreases in endogenous melatonin levels, it is difficult to predict the extent to which nonpharmacologic mind-body therapies would be efficacious if used alone, without consideration of ovarian hormone replacement therapy. The WHI has definitively demonstrated the risks posed by a standard nonphysiologic estrogen/progestin replacement regimen. Subsequent studies have shown that physiologic replacement, administered transdermally with regard to estrogen, testosterone, and progesterone can mitigate these VTE, breast cancer, and cardiovascular risks.
Since endogenous levels of melatonin decrease in temporal sequence to the drop in ovarian sex hormones, physiologic ovarian hormone replacement may positively impact melatonin levels, which are an important input to the quality of sleep, particularly in older individuals. Given the side effects of pharmacologic therapy for insomnia, which include decreasing endogenous melatonin levels and dangerous side effects such as complex, automatic sleep-related behaviors, it is important to get back to basics and consider physiologic replacement of ovarian hormone deficiencies with standardized, bioidentical products for women guided by periodic blood level determinations. It will be important to design randomized, controlled studies to evaluate the effect of these replacement therapies on validated indicators of sleep quality.
Women who present with complaints of insomnia in midlife should have a full endocrinologic evaluation to determine ovarian function. Depending upon their history and physical evaluation, consideration should be given to a polysomnographic evaluation to rule out sleep disordered breathing which may impose cardiovascular risk, and an appropriate work-up should rule out medical or psychiatric causes of insomnia which should be prioritized for treatment. A physician-patient discussion should include the topic of physiologic hormone replacement, with adjustment of the dosages of estrogen, progesterone, and testosterone determined according to measurements of plasma hormone levels. Estrogen and progesterone replacement have had salutary effects on quality of sleep in postmenopausal women. Animal and clinical studies suggest that maintaining physiologic blood levels of testosterone can mitigate the risk of breast cancer that has been seen in estrogen-progestogen replacement regimens.
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