Changes are currently being studied in the use of oral contraceptives (OC) in women under and over 35. At a poster session held in October, 2000, four experts addressed issues related to transitioning from OCs to HRT, and the effect of HRT on osteoporosis, sexual functioning, and breast cancer risk.
This poster session was supported by The Hormone Society, The Endocrine Society, and an unrestricted educational grant from Wyeth-Ayerst Laboratories.
Overview
Most women have several major concerns regarding their menstrual cycle beginning from the onset of menarche to menopause. A poster presentation focused on three general areas - oral contraceptives (OC), hormone replacement therapy (HRT), and quality of life (QOL) issues in the postmenopausal years. Synopses of four poster sessions are presented below.
Currently under study are the changes in the use of oral contraceptives in women under and over 35 and the considerations involved in transitioning women from oral contraceptives to hormone replacement therapy. Increasing emphasis is being placed on the role played by HRT in cholesterol management, osteoporosis, central nervous system disease, and urogenital health, as well as the use of HRT and its association with breast cancer risk. Finally, hormonal changes have implications on sexual function. Although this aspect of the menopause receives little attention, it is an important QOL issue. Alternative menopause treatments are also receiving increasing attention, as aging baby boomers are actively seeking nontraditional remedies.
Modern OCs aim to minimize estrogen-related adverse events and side effects while maintaining efficacy and cycle control. Currently, 20 µg is the lowest available dose of ethinyl estradiol available in OC formulations in the United States that is effective in contraception, well tolerated, and controls the bleeding pattern after the first few cycles of use. There are numerous noncontraceptive benefits of OCs, as well, including reduced risk of certain cancers, improved acne, preservation of bone mineral density, and alleviation of dysmenorrhea.
Women in their early climacteric years have special health needs including contraception and the amelioration of moliminal symptoms, during a time when they may also be starting to experience symptoms of menopause and to lose bone mass. An important clinical consideration related to OC use in the perimenopause is how to switch to HRT and the potential methods for determining the timing of this transition.
Recent clinical trials have found the benefit of the adjunctive use of HRT with statins, both of which produce favorable changes in the serum lipid profile, and, when combined, are more effective than monotherapy with either agent. Current data also show that low-dose HRT can prevent menopause-related bone loss and be associated with better adherence, thus providing long-term benefit. In addition, long-term HRT appears to protect against memory loss and may decrease the prevalence of Alzheimer's disease in postmenopausal women. However, there is considerable debate about the potential impact of HRT on breast cancer development. Researchers continue to add new data to this expanding area of research but, as of yet, there is no definitive answer.
Psychosocial concerns remain the predominant cause of female sexual dysfunction. However, in the menopausal woman, physical changes, notably estrogen deficiency and declining androgen production and the resultant genital atrophy and decreased libido, may be contributing factors.
As female baby boomers age, many are searching for untraditional menopause treatments. Other women who desire such therapies may seek an alternative to estrogen replacement therapy (ERT) for medical reasons, such as breast cancer history or intolerance to ERT. Soy and black cohosh are two alternatives that may help alleviate menopausal symptoms.
When to Transition from Oral Contraceptives to Hormone Replacement Therapy
As huge numbers of American women approach menopause, many physicians are faced with determining why, when, and how a woman should be switched from a combination OC to HRT. Within this context, the challenging issues when treating perimenopausal women are how to detect the onset of menopause in a woman taking combination OCs and when to transition a woman from OCs to HRT.
Perimenopause is often defined as a time of declining ovarian function and follicle depletion that may precede menopause by 2 to 8 years. With perimenopause, ovarian estradiol production, inhibin levels, and cycle length decrease while follicle stimulating hormone (FSH) and luteinizing hormone (LH) increase. As a result, oligomenorrhea and anovulatory uterine bleeding usually occur. Menopause is defined as the cessation of menses for > 12 months, with 51 years as the average age when this occurs in women in the United States.
Pregnancy after age 40 presents a number of risks, including increased rates of underlying disorders, such as diabetes mellitus, and higher rates of placenta previa, operative delivery, and maternal mortality. After age 34, the percent of unintended pregnancies increases with age. In fact, the rate of abortion in women Ž 40 years old is the same as that in teens; approximately 30% to 35% of pregnancies in both groups end in abortion. While OCs can prevent unintended pregnancy in perimenopausal women, HRT does not.
Perimenopausal OCs are associated with several benefits. They may relieve many of the symptoms of menopause, including hot flashes and vaginal dryness, and may also reduce the risk of endometrial and epithelial cancers, improve bone density, and control menorrhagia.
When the potential for pregnancy is no longer a concern, HRT is preferable to OCs because HRT uses the lowest effective estrogen dosage needed to treat menopausal symptoms and less progestin. Epidemiologic evidence suggests that HRT may provide primary protection against cardiovascular disease and osteoporosis. Finally, venous thromboembolism risk may be greater in menopausal women using OCs compared to HRT.
It is crucial, however, to understand menopausal status before transitioning a patient from OCs to HRT to avoid both the unnecessary risk of pregnancy and the unpleasantness of menopausal symptoms. Blood tests, specifically FSH, are not reliable indicators because levels fluctuate
between reproductive-age and menopausal levels throughout perimenopause, and from month to month. Other potential tests include estradiol levels and the FSH/LH ratio; the menopausal estradiol level is < 25 pg/ml in most assays, and the meno-pausal FSH/LH ratio is > 1.
Studies have attempted to identify if these other blood tests may be more reliable than FSH to indicate menopause without discontinuing the use of OCs. In a study evaluating the hypothalamo-pituitary axis in reproductive-age women on low-dose combination OCs, FSH and LH were undetectable on day 1 of placebo week but were back to normal (same as controls) by day 7. Estradiol levels were in the follicular phase levels but were still suppressed compared to controls. However, in menopausal women, FSH levels do not reliably return to the menopausal range by day 7, but estradiol levels are still < 25 pg/ml and the FSH/LH ratio is > 1. Thus, one could assume that to evaluate for menopause in a woman taking OCs, blood tests can be performed on day 7 of the pill-free interval to determine both the estradiol level and FSH/LH ratio. However, these tests are also not reliable because they would only indicate that a woman's hormonal status is menopausal at that moment in time. If she is truly just perimenopausal, then she could have a different hormonal pattern and even ovulate in the ensuing few months.
The transition from OCs to HRT must be individualized for every patient. Factors other than blood test results, such as age, need for contraception, and other medical history will likely be instrumental in aiding in the decision of when to change treatments.
The Backbone of the Journey: Bone Benefits with Low-Dose HRT
Postmenopausal osteoporosis affects more than 25 million women in the United States alone. HRT is a cornerstone of postmenopausal osteoporosis prevention and treatment. However, standard doses of estrogen are associated with certain side effects, such as PMS-type symptoms, unwanted bleeding, and a small potential increased risk of breast cancer.
Investigators have studied the possibility that low-dose HRT (< 0.625 mg conjugated equine estrogens [CEE]) may protect against bone loss while minimizing or eliminating unwanted side effects. Studies demonstrate that low-dose HRT can either prevent bone loss typically seen postmenopausally, or slightly increase bone mass.
Current data suggest that the influence of HRT on bone mineral density (BMD), lipids, and the development of endometrial hyperplasia may be dose-related. For instance, the beneficial effect of HRT on bone mass increases with increasing dosages of estrogen. Genant and colleagues found that the BMD of the lumbar spine increased 1.76%, 2.81%, and 5.10% in the 0.3 mg, 0.625 mg, and 1.25 mg esterified estrogens group after 24 months of therapy, respectively, and decreased 2.52% in the placebo group.
Progestin may have a synergistic effect on BMD when used with estrogen. Speroff et al reported that norethindrone acetate plus ethinyl estradiol (EE2) produced a dose-related BMD increase not seen with unopposed EE2. A separate randomized trial of 81 postmenopausal women showed that a low-dose combination of CEE 0.3 mg plus medroxyprogesterone (MPA) 10 mg and calcium produced a preservative effect on BMD that was similar to CEE 0.625 mg plus calcium after 4.4 years of therapy.
Data also suggest that adequate calcium and vitamin D intake may enhance the BMD response to low-dose HRT. Recker and colleagues cited their approach to calcium and vitamin D supplementation as a possible reason why they reported the most positive BMD response to low-dose HRT to date. Prestwood et al demonstrated that calcium, when given with estrogen, further reduced bone resorption but did not influence bone formation vs estrogen alone in women > 70 years old.
In sum, low-dose HRT can help prevent bone loss in postmenopausal women. It may even be beneficial for older postmenopausal women who have been estrogen deficient for some time. The lowest effective HRT dose should be considered an appropriate choice for women who require HRT. Conventional higher doses of HRT should be reserved for newly menopausal women and those who need control of moderate to severe hot flashes or who have documented osteopenia/osteoporosis.
The Road Less Traveled: Menopause and Sexual Dysfunction
Interpersonal factors remain the predominant cause of female sexual dysfunction, and simple behavioral therapy is surprisingly effective. However, as women undergo menopause, hormonal changes can play an important role in sexual function. Every female subjected to estrogen deficiency will develop genital atrophy, and androgen loss may contribute to decreased libido.
Most women do not lose interest in sex simply because they are aging but the resulting sexual dysfunction at menopause can diminish quality of life. Genital urinary atrophy-and the accompanying urinary and sexual dysfunction-is the most inevitable and least publicized consequence of estrogen deficiency. In fact, the highest concentration of estrogen receptors in the body is in the vulva, vagina, urethra, and trigone of the bladder. In an estrogen-deficient environment, atrophy of the epithelium becomes evident rapidly, while connective-tissue atrophy develops insidiously after years of estrogen deficiency. Both superficial and structural atrophy can contribute to urogenital dysfunction including vaginal dryness, frequency and urgency and, after several years, dyspareunia and arterial insufficiency (vaginal and clitoral erectile insufficiency syndrome).
Prevention and early treatment of genital atrophy are important. Every postmenopausal woman should consider taking estrogen replacement therapy (ERT) for the prevention of genital atrophy. If there is arousal-phase dysfunction, it is especially important to begin treatment early to prevent dyspareunia. Disuse atrophy can compound the problem.
Superficial atrophic changes respond rapidly to ERT. Vaginal pH can normalize with as little as 3 months of therapy, indicating the return of healthy vaginal epithelium. In fact, as little as two to three applications per week of local estrogen vaginal cream can restore mature epithelium. Atrophic connective tissue changes also respond to ERT. Vaginal fluid production and its potassium content can continue to improve for up to 6 months after initiation of ERT.
Although most women respond to ERT alone, combination androgen/ ERT may be considered for the oophorectomized woman who continues to experience decreased libido despite ERT. Often, supraphysiologic doses of androgen are needed to not only replace androgen lost through menopause but also to enhance libido. Two controlled clinical studies of supraphysiologic doses of testosterone enanthate in combination with IM estradiol valerate demonstrated that surgically menopausal women had higher rates of sexual desire, arousal and fantasies (P < 0.01 in one study) than women who received estrogen alone. Other possible benefits of androgen therapy include increased BMD when used with estrogen; diminution of ERT-induced mastalgia, treatment of refractory headaches, and increased energy. Ideal androgen therapy has not yet been determined, and individualization increases the likelihood of success. The detrimental effects of supraphysiologic levels of androgen, including effects on lipids and on acne and hirsutism, must be considered if such therapy is contemplated
Curves in the Road: HRT and Breast Cancer Risk
Between 1991 and 1995, the mortality rate from breast cancer declined by 4.6%, thanks to improvements in cancer treatment and increased awareness and detection. Nevertheless, there is still considerable debate about the potential impact of HRT on breast cancer development, and physicians and postmenopausal women commonly discontinue HRT out of fear that the therapy may increase breast cancer risk.
To objectively assess all available evidence, it is often productive to compare new data to the existing literature and determine if new results represent a departure from or a confirmation of earlier research. Meta-analyses of ERT/HRT use and breast cancer risk have suggested that estrogen replacement and estrogen plus progestin therapy are associated with a slightly increased risk of breast cancer. New breast cancer study results indicate that the overall risk of breast cancer appears consistent with that reported in the earlier literature (Figure 1).
Existing and new observational evidence suggests that the addition of progestin to the ERT regimen may increase breast cancer risk. Results from the Breast Cancer Detection Demonstration Project indicate that when compared with controls (no use of hormones), the relative risk ranged from 1.1 (1.0-1.3) for estrogen-only to 1.3 (1.0-1.6), 1.2 (1.0-1.5) and 0.9 (0.5-1.6) for estrogen-progestin only, estrogen alone + estrogen-progestin, and progestin only, respectively.
New data suggest that the progestin dose/regimen may influence breast cancer risk. The University of Southern California Study indicates that sequential HRT may confer a greater risk than continuous combined HRT. The risk, based on 1-5 years of hormone use, was 1.02, 1.19, and 0.88 for ERT, sequential HRT, and continuous combined HRT, respectively. For use from 5 to 10 years, the risk was 0.94, 1.58, and 1.28, respectively for ERT, sequential HRT, and continuous combined HRT. New data from the NHANES study suggest that the duration of HRT use does not influence risk. Relative risk ranged from 0.8 (0.6-10.1) for ever-used to 0.8 (0.5-1.3) for use 10 years or more.
As more breast cancers are detected at an earlier stage and are now often curable, menopausal symptoms have become an increasingly important issue. Breast cancer patients have the same menopausal symptoms as patients without breast cancer, and as many as 30% to 40% would consider hormone therapy for symptom alleviation.
Progestin is clearly protective of the endometrium but may possibly be deleterious to the breast when added to estrogen. The progestin type, dose, and regimen may affect breast cancer risk. Individual discussion with patients about the risk and benefits of HRT is needed. Hopefully, the Women's Health Initiative Study will shed further light on this issue.
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