Patient's informed choice is a key to good care in the transitional years.
The patient's informed choice is a key to good care in the transitional years. Women deserve to know the facts and need help in dealing with the state of the art.
There has been considerable confusion in defining the perimenopausal transition. I prefer to use menstrual irregularity as a marker because data from longitudinal studies provide an objective designation that can be used to define and establish what is called the perimenopausal transition. Thus, the years prior to menopause that encompass the change from normal ovulatory cycles to cessation of menses are known as the perimenopausal transitional years, marked by irregularity of menstrual cycles. Our best information comes from two longitudinal studies (with very similar results): the study of Vollman of more than 30,000 cycles recorded by 650 women and the study of Treloar of more than 25,000 woman-years in slightly more than 2,700 women.1,2 The observations of Vollman and Treloar documented a normal evolution in length and variation in menstrual cycles.
Menarche is followed by approximately 5 to 7 years of relatively long cycles at first, and then there is increasing regularity as cycles shorten to reach the usual reproductive-age pattern. In the 40s, cycles begin to lengthen again. The highest incidence of anovulatory cycles is under age 20 and over age 40.3,4 In the longitudinal Massachusetts Women's Health Study, women who reported the onset of menstrual irregularity were considered to be in the perimenopausal period of life.5 The median age for the onset of this transition was 47.5 years. Only 10% of women ceased menstruating abruptly with no period of prolonged irregularity. The perimenopausal transition from reproductive to postreproductive status was, for most women, approximately 4 years in duration. In the study by Treloar, the average age for entry into the perimenopausal transition was 45.1, and the age range that included 95% of the women was 39 to 51.6 The mean duration of the perimenopausal transition was 5 years, with a range of 2 to 8 years (Table 1).2,5,6
When women are in their 40s, anovulation becomes more prevalent and, prior to anovulation, menstrual cycle length increases, beginning 2 to 8 years before menopause.2 This period of longer cycles uniformly precedes menopause no matter the age when menses cease, whether menopause is early or late.7 The duration of the follicular phase is the major determinant of cycle length.8,9 This menstrual cycle change prior to menopause is marked by elevated FSH levels and decreased levels of inhibin, but normal levels of LH and slightly elevated levels of estradiol.10-14
Contrary to older belief (based on the report by Sherman and colleagues8), estradiol levels do not gradually wane in the years before menopause, but remain in the normal range, although slightly elevated, until 6 months to 1 year before follicular growth and development cease.14-17 Indeed, women experiencing the perimenopausal transition actually have higher overall estrogen levels, a response that is logically explained by an increased ovarian follicular response to the increase in FSH secretion during these years.15, 18
As noted, most women experience a 2- to 8-year period of time prior to menopause when anovulation becomes prevalent.2 During this period of time, ovarian follicles undergo an accelerated rate of loss until eventually the supply of follicles is finally depleted.19,20 In a study of human ovaries, the accelerated loss appeared to begin when the total number of follicles reached approximately 25,000, a number reached in normal women at age 37 to 38.21 This loss correlates with a subtle but real increase in FSH and decrease in inhibin. The accelerated loss is probably secondary to the increase in FSH stimulation.
These changes, including the increase in FSH, reflect the reduced quality and capability of aging follicles, and their reduced secretion of inhibin, the granulosa cell product that exerts an important negative feedback influence over FSH secretion by the pituitary gland. Both inhibin A and inhibin B may be involved. Luteal-phase levels of inhibin A and follicular phase levels of inhibin B decrease with aging, and may antedate the rise in FSH.22-24
The inverse and tight relationship between FSH and inhibin indicates that inhibin is a sensitive marker of ovarian follicular competence and, in turn, that FSH measurement is a clinical assessment of inhibin. Thus, the changes in the later reproductive years (the decline in inhibin allowing a rise in FSH) reflect diminishing follicular reactivity and competence as the ovary ages.11,12 The decrease in inhibin secretion by the ovarian follicles begins early (around age 35), but accelerates after 40 years of age. This is reflected in the decrease in fecundity that occurs with aging. Furthermore, the ineffective ability to suppress gonadotropins with postmenopausal hormone therapy is a consequence of the loss of inhibin, and for this reason FSH cannot be used clinically to titer estrogen dosage.
The perimenopausal years are a time period during which postmenopausal levels of FSH (>20 IU/L) can be seen despite continued menstrual bleeding, while LH levels still remain in the normal range. Occasionally, corpus luteum formation and function occur, and the perimenopausal woman is not safely beyond the risk of an unplanned and unexpected pregnancy until elevated levels of both FSH (>20 IU/L) and LH (>30 IU/L) can be demonstrated.13 However, even under these circumstances, fluctuations can occur, with a period of ovarian failure followed by resumption of ovarian function.12,25 Because variability is the rule, it would be wise to recommend the use of contraception until the postmenopausal state is definitely established.
Throughout the transitional period of life there is a significant incidence of dysfunctional uterine bleeding (DUB) due to anovulation. While the clinician is usually alerted to this problem because of irregular bleeding, clinician and patient often fail to diagnose anovulation when bleeding is not abnormal in schedule, flow, or duration. As a woman approaches menopause, a more aggressive attempt to document ovulation is warranted. A serum progesterone level measured approximately 1 week before menses is simple enough to obtain and worth the cost. The prompt diagnosis of anovulation (serum progesterone <300 ng/dL) will lead to appropriate therapeutic management that will have a significant impact on the risk of endometrial cancer.
In an anovulatory woman with DUB associated with proliferative or hyperplastic endometrium (uncomplicated by atypia or dysplastic constituents), periodic oral progestin therapy is mandatory, such as 5 to 10 mg medroxyprogesterone acetate given daily for at least the first 10 days of each month. If hyperplasia is present, follow-up aspiration curettage after 3 to 4 months is required. The follow-up biopsy should be performed 1 to 2 months after the progestin treatment to allow any progestin-induced masking of atypia to recede. If progestin is ineffective and histological regression is not observed, formal curettage is an essential preliminary to alternate therapeutic surgical choices. Because hyperplasia with atypia carries with it a risk of invasive cancer, hysterectomy is the treatment of choice.
When monthly progestin therapy reverses hyperplastic changes (which it does in 95% to 98% of cases) and controls irregular bleeding, treatment should be continued until withdrawal bleeding ceases. This is a reliable sign (in effect, a bioassay) indicating the onset of estrogen deprivation and the need for the addition of estrogen. If vasomotor disturbances begin before the cessation of menstrual bleeding, the combined estrogen-progestin program can be initiated as needed to control the flushes.
Two case-control studies, one using data from the WHO Collaborative Study and one using the data from the United Kingdom general practices research database, assessed the risk of idiopathic venous thrombosis (VTE) in users of progestins alone for therapeutic purposes and concluded that therapeutic progestins alone may be associated with an increased risk of venous thromboembolism.26,27 These epidemiologic conclusions were based on extremely small numbers and had very wide confidence intervals. Patients who receive progestin only for therapeutic reasons are probably older and are more likely to have family histories of cardiovascular disease. In addition, a problem of preferential prescribing is probably present in that clinicians are more likely to promote the use of progestin-only treatment for women they perceive to be at greater risk of VTE. Thus, it is likely that the case groups represented a higher-risk group than the control groups in these reports. For these reasons, progestins are not believed to be associated with an increased risk of VTE.
If contraception is required, the healthy, nonsmoking patient should seriously consider the use of oral contraception. The anovulatory woman cannot be sure that spontaneous ovulation and pregnancy will not occur. The use of a low-dose OC will at the same time provide contraception and prophylaxis against irregular, heavy anovulatory bleeding and the risk of endometrial hyperplasia and neoplasia. Indeed, many clinicians believe more effective control of menstrual irregularity is achieved with OCs compared with periodic monthly progestin treatment.
Clinicians often prescribe a traditional postmenopausal HRT regimen to treat a woman with the kind of irregular cycles usually experienced in the perimenopausal years. This addition of exogenous estrogen without a contraceptive dose of progestin when a woman is not amenorrheic or experiencing menopausal symptoms is inappropriate and even risky (exposing the endometrium to excessively high levels of estrogen). And most importantly, postmenopausal HRT does not inhibit ovulation and provide contraception.28 The appropriate response is to regulate anovulatory cycles with monthly progestational treatment along with an appropriate contraceptive method or to use low-dose OCs. OCs that contain 20 µg of estrogen provide effective contraception, improve menstrual cycle regularity, diminish bleeding, and relieve menopausal symptoms.29
In a longitudinal follow-up study of a large number of women, fully 10% of the women experienced hot flushes before menopause, while in other studies as many as 15% to 25% of premenopausal women reported hot flushes.5, 30-32 The frequency has been reported to be even higher in premenopausal women previously diagnosed with premenstrual syndrome.33 In the Massachusetts Women's Health Study, the incidence of hot flushes increased from 10% during the premenopausal period to about 50% just after cessation of menses.5 By approximately 4 years after menopause, the rate of hot flushes declined to 20% (Table 2). In a community-based Australian survey, 6% of premenopausal women, 26% of perimenopausal women, and 59% of postmenopausal women reported hot flushing.34
12 years average
5+ years in 25%
The physiology of the hot flush is still not understood, but it apparently originates in the hypothalamus and is brought about by a decline in estrogen. Not all hot flushes, however, are due to estrogen deficiency. Flushes and sweating can be secondary to diseases, including pheochromocytoma, carcinoids, leukemias, pancreatic tumors, and thyroid abnormalities.35 Unfortunately, the hot flush is a relatively common psychosomatic symptom, and women often are unnecessarily treated with estrogen. When the clinical situation is not clear and obvious, estrogen deficiency as the cause of hot flushes can be documented by elevated levels of FSH.
Premenopausal women experiencing hot flushes should be screened for thyroid disease and other illnesses. A comprehensive review of all possible causes is available.36 Clinicians should be sensitive to the possibility of an underlying emotional problem. Looking beyond the presenting symptoms into the patient's life will be an important service to the patient and her family that eventually will be appreciated. This is far more difficult than simply prescribing estrogen, but confronting problems is the only way of reaching some resolution. Prescribing estrogen inappropriately (in the presence of normal levels of gonadotropins) only temporarily postpones dealing with the underlying issues by relying on a placebo response.
A striking and consistent finding in most studies dealing with menopause and hormonal therapy is a marked placebo response in a variety of symptoms, including flushing. In an English randomized, placebo-controlled study of women being treated with estrogen implants and requesting repeat implants, there was no difference in outcome in terms of psychological and physical symptoms comparing the women who received an active implant to those receiving a placebo.37
A significant clinical problem encountered in my practice is the following scenario: A woman will occasionally undergo an apparent beneficial response to estrogen, only to have the response wear off in several months. This leads to a sequence of periodic office visits and ever-increasing doses of estrogen. When a patient reaches a point of requiring large doses of estrogen, a careful inquiry must be undertaken to search for a basic psychoneurotic or psychosocial problem. To help persuade a patient that her symptoms are not due to low levels of estrogen, we find it very helpful and convincing to measure the patient's blood level of estradiol and share the result with her.
Evidence is accumulating that treatment with selective serotonin-reuptake inhibitors is very effective for the treatment of hot flushes.38-41 The efficacy of the lowest-dose tablet of each agent given daily is almost comparable to that of estrogen. This provides clinicians with a good treatment choice for hot flushes when patients cannot or will not use HRT.
The view that menopause has a deleterious effect on mental health is not supported in the psychiatric literature, or in surveys of the general population.30,31,42,43 The concept of a specific psychiatric disorder (involutional melancholia) has been abandoned. Indeed, depression is less common, not more common, among middle-aged women, and menopause cannot be linked to psychological distress.32,44-50 The longitudinal study of premenopausal women indicates that hysterectomy with or without oophorectomy is not associated with a negative psychological impact among middle-aged women.51 And longitudinal data from the Massachusetts Women's Health Study document that menopause is not associated with an increased risk of depression.52 Although women are more likely to experience depression than men, this sex difference begins in early adolescence not at menopause.53
The U.S. National Health Examination Follow-up Study includes both longitudinal and cross-sectional assessments of a nationally representative sample of women. This study has found no evidence linking either natural or surgical menopause to psychologic distress.54 Indeed, the only longitudinal change was a slight decline in the prevalence of depression as women aged through the menopausal transition. Results in this study were the same in estrogen users and nonusers.
A negative view of mental health at the time of the menopause is not justified; many of the problems reported at the menopause are due to the vicissitudes of life.55, 56 Thus, there are problems encountered in early postmenopause that are seen frequently, but their causal relation with estrogen is unlikely. These problems include fatigue, nervousness, headaches, insomnia, depression, irritability, joint and muscle pain, dizziness, and palpitations. Indeed, men and women at this stage of life both express a multitude of complaints, which do not reveal a gender difference that could be explained by a hormonal cause.57
Attempts to study the effects of estrogen on these problems have been hampered by the subjectivity of the complaints (high placebo responses) and the "domino effect" of what reduction of hot flushes does to the frequency of the symptoms. Using a double-blind prospective, crossover study format, Campbell and Whitehead concluded many years ago that many symptomatic "improvements" ascribed to estrogen therapy result from relief of hot flushesa "domino" effect.58
A study of 2,001 Australian women aged 45 to 55 focused on the utilization of the health-care system by women in the perimenopausal period of life.59 Users of the health-care system in this age group were frequent previous users of health care, less healthy, and had more psychosomatic symptoms and vasomotor reactions. These women were more likely to have had a significant previous adverse health history, including a past history of premenstrual complaints. This study emphasized that perimenopausal women who seek health-care help are different from those who do not seek help, and they often embrace HRT in the hope it will solve their problems.
Similar findings have been reported in a cohort of British women.60 It is this population that is seen most often by clinicians, producing biased opinions regarding the menopause among physicians. We must be careful not to generalize to the entire female population the behavior experienced by this relatively small group of women. Most importantly, perimenopausal women who present to clinicians often end up being inappropriately and unnecessarily treated with estrogen. Nevertheless, it is well-established that a woman's quality of life is disrupted by vasomotor symptoms, and estrogen therapy provides impressive improvement.61,62 Patients are grateful to be the recipients of this "domino" effect.
Emotional stability during the perimenopausal period can be disrupted by poor sleep patterns. Hot flushing does have an adverse impact on the quality of sleep.63 Estrogen therapy improves the quality of sleep, decreasing the time to onset of sleep and increasing the rapid eye movement (REM) sleep time.61,64,65 Perhaps flushing may be insufficient to awaken a woman but sufficient to affect the quality of sleep, thereby diminishing the ability to handle the next day's problems and stresses. An improvement in insomnia with estrogen treatment can even be documented in postmenopausal women who are reportedly asymptomatic.65
Thus, the overall "quality of life" reported by women can be improved by better sleep and alleviation of hot flushing. However, it is still uncertain whether estrogen treatment has an additional direct pharmacologic antidepressant effect or whether the mood response is an indirect benefit of relief from physical symptoms and, consequently, improved sleep. Using various assessment tools for measuring depression, improvements with estrogen treatment have been recorded in oophorectomized women.66,67 In the large prospective cohort study of the Rancho Bernardo retirement community, no benefit could be detected in measures of depression in current users of postmenopausal estrogen compared with untreated women.68 Indeed, treated women had higher depressive symptom scores, presumably reflecting treatment selection bias; symptomatic and depressed women seek HRT. Nevertheless, estrogen therapy is reported to have a more powerful impact on women's well-being beyond the relief of symptoms such as hot flushes.69
Besides fulfilling a need for contraception, older women have many benefits to be derived from OCs that tilt the risk:benefit ratio to the positive side (Table 3). An approach that emphasizes these benefits will encourage greater use of OCs by older women.
Despite the widespread teaching and publicity that smoking is a contraindication to OC use over the age of 35, more older women who use OCs smoke and smoke heavily, compared with young women.70 This strongly implies that older smokers are less than honest with clinicians when requesting OCs. A former smoker must have stopped smoking for at least 12 consecutive months to be regarded as a nonsmoker. Women who have nicotine in their bloodstream obtained from patches or gum should be regarded as smokers. Smokers over age 35 should continue to be advised that combined OCs are not a good choice, regardless of the number of cigarettes smoked.71, 72 In view of the unreported high rate of smoking in older women who use OCs, clinicians should consider using 20-µg estrogen products for all women over age 35.
A product containing 20 µg ethinyl estradiol and 150 µg desogestrel has been demonstrated in multicenter studies of women over age 30 to have the same efficacy and side effects as pills containing 30 and 35 µg of estrogen.73-75 In a randomized study of women over age 30, this formulation was associated with the virtual elimination of any effects on coagulation factors.76 Indeed, the 20-µg formulation has no significant impact on the measurements of clotting factors, even in smokers.76-79
Although it is true that the implied safety of the lowest estrogen dose remains to be documented by epidemiologic studies, it seems clinically prudent to maximize the safety margin in this older age group of women. Although there may be some increase in breakthrough bleeding, older women who need and understand the increased safety implicit in the lowest estrogen dose are more willing to endure breakthrough bleeding and maintain continuation. With avoidance of risk factors and use of lowest-dose pills, health risks are probably negligible for healthy nonsmoking women. For healthy nonsmoking women, no specific laboratory screening is necessary, beyond that which is usually incorporated in a program of preventive health care.
A common clinical dilemma is when to change from OCs to HRT. It is important to change because even with the lowest-estrogen-dose OCs available, the estrogen dose is four-fold greater than the standard postmenopausal dose, and with increasing age, the dose-related risks with estrogen become significant. One approach to establish the onset of the postmenopausal years is to measure the FSH level, beginning at age 50, on an annual basis, being careful to obtain the blood sample on day 6 or 7 of the pill-free week (when steroid levels have declined sufficiently to allow FSH to rise). Friday afternoon works well for patients who start new packages on Sunday. When FSH is greater than 20 IU/L, it is time to change to a postmenopausal hormone program. Because of the variability in FSH levels experienced by women around the menopause, this method is not always accurate.25,80,81 Indeed, a totally reliable FSH level requires 2 weeks to elapse after the last pill. This is not very practical and places the patient at risk for an unwanted pregnancy. The pill-free-week method is practical and works for most women. Some clinicians are comfortable allowing patients to enter their mid-50s on low-dose OCs, and then empirically switching to a postmenopausal HRT.
Preventive intervention during the perimenopausal years has three major goals. The overall objective is to prolong the period of maximal physical energy and optimal mental and social activity. A specific goal is to detect as early as possible any of the major chronic diseases, including hypertension, heart disease, diabetes mellitus, and cancer, as well as impairments of vision, hearing, and teeth. Finally, the clinician should help perimenopausal women to smoothly traverse the menopausal period of life.
The issues of preventive health care are familiar ones. They include contraception, cessation of smoking, prevention of heart disease and osteoporosis, maintenance of mental well-being (including sexuality), and cancer screening. Management of the transition years should be significantly oriented to preventive health care, and the use of low-dose OCs can now legitimately be viewed as a component of preventive health care. A discussion of the noncontraceptive health benefits of low-dose OCs is especially important with patients in their transition years. This group of women appreciates and understands decisions made with the risk:benefit ratio in mind. For example, a useful observation to bring to our patient's attention is the following: Continuous use of OCs for 10 years by women with a positive family history for ovarian cancer can reduce the risk of epithelial ovarian cancer to a level equal to or less than that experienced by women with a negative family history.82
The patient's informed choice is a key to good care in the transitional years. Patients deserve to know the facts and need help in dealing with the state of the art and the uncertainty expressed in the media's coverage of research findings. But there is no doubt that patients are influenced in their choice by their clinician's advice and attitude. While the role of a clinician is to provide the education necessary for the patient to make proper choices, one should not lose sight of the powerful influence exerted by the clinician in the choices ultimately made. An emphasis on preventive health care can have a major impact on lifestyle and healthcare decisions.
1. Vollman RF. The menstrual cycle. In: Friedman E, ed. Major Problems in Obstetrics and Gynecology. Philadelphia, Pa; W.B. Saunders Co: 1977.
2. Treloar AE, Boynton RE, Behn BG, et al. Variation of the human menstrual cycle through reproductive life. Int J Fertil. 1970;12:77-126.
3. Collett ME, Wertenberger GE, Fiske VM. The effect of age upon the pattern of the menstrual cycle. Fertil Steril. 1954;5:437.
4. Chiazze Jr L, Brayer FT, Macisco Jr JJ, et al. The length and variability of the human menstrual cycle. JAMA. 1968;203:377-380.
5. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas. 1992;14:103-115.
6. Treloar AE. Menstrual cyclicity and the pre-menopause. Maturitas. 1981;3:249-264.
7. den Tonkelaar I, te Velde ER, Looman CW. Menstrual cycle length preceding menopause in relation to age at menopause. Maturitas. 1998;29:115-123.
8. Sherman BM, West JH, Korenman SG. The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. J Clin Endocrinol Metab. 1976;42:629-636.
9. Lenton EA, Landgren B, Sexton L, et al. Normal variation in the length of the follicular phase of the menstrual cycle: effect of chronological age. Br J Obstet Gynaecol. 1984;91:681-684.
10. Buckler HM, Evans A, Mamlora H, et al. Gonadotropin, steroid and inhibin levels in women with incipient ovarian failure during anovulatory and ovulatory 'rebound' cycles. J Clin Endocrinol Metab. 1991;72:116-124.
11. MacNaughton J, Bangah M, McCloud P, et al. Age-related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and immunoreactive inhibin in women of reproductive age. Clin Endocrinol. 1992;36:339-345.
12. Hee J, MacNaughton J, Bangah M, et al. Perimenopausal patterns of gonadotrophins, immunoreactive inhibin, oestradiol and progesterone. Maturitas. 1993;18:9-20.
13. Metcalf MG, Livesay JH. Gonadotropin excretion in fertile women: effect of age and the onset of the menopausal transition. J Endocrinol. 1985;105:357-362.
14. Rannevik G, Jeppsson S, Johnell O, et al. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas. 1995;21:103-113.
15. Burger HG, Cahir N, Robertson DM, et al. Serum inhibins A and B fall differentially as FSH rises in perimenopausal women. Clin Endocrinol. 1998;48:809-813.
16. Burger HG, Dudley EC, Hopper JL, et al. Prospectively measured levels of serum follicle-stimulating hormone, estradiol, and the dimeric inhibins during the menopausal transition in a population-based cohort of women. J Clin Endocrinol Metab. 1999;84:4025-4030.
17. Burger HG, Dudley E, Manners P, et al. Early follicular phase serum FSH as a function of age: the roles of inhibin B, inhibin A and estradiol. Climacteric. 2000;3:17-24.
18. Santoro N, Brown JR, Adel T, et al. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab. 1996;81:1495-1501.
19. Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the menopausal transitionevidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab. 1987;65:1231-1237.
20. Gougeon A, Echochard R, Thalabard JC. Age-related changes of the population of human ovarian follicles: increase in the disappearance rate of non-growing and early-growing follicles in aging women. Biol Reprod. 1994;50:653-663.
21. Faddy MJ, Gosden RG, Gougeon A, et al. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod. 1992;7:1342-1346.
22. Klein NA, Illingworth PJ, Groome NP, et al. Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles. J Clin Endocrinol Metab. 1996;81: 2742-2745.
23. Danforth DR, Arbogast LK, Mroueh J, et al. Dimeric inhibin: a direct marker of ovarian aging. Fertil Steril. 1998;70:119-123.
24. Welt CK, McNicholl DJ, Taylor AE, et al. Female reproductive aging is marked by decreased secretion of dimeric inhibin. J Clin Endocrinol Metab. 1999;84:105-111.
25. Burger HG. Diagnostic role of follicle-stimulating hormone (FSH) measurements during the menopausal transitionan analysis of FSH, oestradiol and inhibin. Eur J Endocrinol. 1994;130:38-42.
26. Poulter NR, Chang CL, Farley TM, et al. Risk of cardiovascular diseases associated with oral progestagen preparations with therapeutic indications. Lancet. 1999;354:1610.
27. Vasilakis C, Jick H, del Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet. 1999;354:1610-1611.
28. Gebbie AE, Glasier A, Sweeting V. Incidence of ovulation in perimenopausal women before and during hormone replacement therapy. Contraception. 1995;52:221-222.
29. Casper RF, Dodin S, Reid RL, and Study Investigators. The effect of 20 mg ethinyl estradiol/1 mg norethindrone acetate (MinnestrinÔ), a low-dose oral contraceptive, on vaginal bleeding patterns, hot flashes, and quality of life in symptomatic perimenopausal women. Menopause. 1997;4:139-147.
30. Hunter M. The South-East England longitudinal study of the climacteric and postmenopause. Maturitas. 1992;14:17-26.
31. Oldenhave A, Jaszmann LJ, Haspels AA, et al. Impact of climacteric on well-being. Am J Obstet Gynecol. 1993;168:772-780.
32. Dennerstein L, Smith AMA, Morse C, et al. Menopausal symptoms in Australian women. Med J Aust. 1993;159:232-236.
33. Hahn PM, Wong J, Reid RL. Menopausal-like hot flashes reported in women of reproductive age. Fertil Steril. 1998;70:913-918.
34. Guthrie JR, Dennerstein L, Hopper JL, et al. Hot flushes, menstrual status, and hormone levels in a population-based sample of midlife women. Obstet Gynecol. 1996;88:437-442.
35. Wilkin JR. Flushing reactions: consequences and mechanisms. Ann Intern Med. 1981;95:468-476.
36. Mohyi D, Tabassi K, Simon J. Differential diagnosis of hot flashes. Maturitas. 1997;27:203-214.
37. Pearce J, Hawton K, Blake F, et al. Psychological effects of continuation versus discontinuation of hormone replacement therapy by estrogen implants: a placebo-controlled study. J Psychosom Res. 1997;42:177-186.
38. Plouffe Jr L, Trott EA, Sanal S, et al. Sertraline (Zoloft) for the management of hot flashes in women on tamoxifen: a randomized controlled pilot trial (abstract). Menopause. 1997;4:262.
39. Loprinzi CL, Pisansky TM, Fonseca R, et al. Pilot evaluation of venlafaxine hydrochoride for the therapy of hot flashes in cancer survivors. J Clin Oncol. 1998;16:2377-2381.
40. Stearns V, Isaacs C, Rowland J, et al. A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil®) in controlling hot flashes in breast cancer survivors. Ann Oncol. 2000;11:17-22.
41. Loprinzi CL, Quella SK, Sloan JA, et al. Preliminary data from a randomized evaluation of fluoxetine (Prozac) for treating hot flashes in breast cancer survivors. Annual Meeting, American Society of Clinical Oncology. San Antonio, Tex:2000.
42. Ballinger CB. Psychiatric aspects of the menopause. Br J Psychiatr. 1990;156:773-787.
43. Schmidt PJ, Rubinow DR. Menopause-related affective disorders: a justification for further study. Am J Psychiatr. 1991;148:844-854.
44. Hällström T, Samuelsson S. Mental health in the climacteric. The longitudinal study of women in Gothenburg. Acta Obstet Gynecol Scand. (Suppl) 1985;130:13-18.
45. Gath D, Osborn M, Bungay G, et al. Psychiatric disorder and gynaecological symptoms in middle aged women: a community survey. Br Med J. 1987;294:213-218.
46. McKinlay SM, McKinlay JB. The impact of menopause and social factors on health. In: Hammond CB, Haseltine FP, Schiff I, eds. Menopause: Evaluation, Treatment, and Health Concerns. New York, NY; Alan R. Liss: 1989.
47. Matthews KA, Wing RR, Kuller LH, et al. Influences of natural menopause on psychological characteristics and symptoms of middle-aged healthy women. J Consult Clin Psychol. 1990;58:345-351.
48. Koster A. Change-of-life anticipations, attitudes, and experiences among middle-aged Danish women. Health Care Women Int. 1991;12:1-13.
49. Holte A. Influences of natural menopause on health complaints: a prospective study of healthy Norwegian women. Maturitas. 1992;14:127-141.
50. Kaufert PA, Gilbert P, Tate R. The Manitoba Project: a re-examination of the link between menopause and depression. Maturitas. 1992;14:143-155.
51. Everson SA, Matthews KA, Guzick DS, et al. Effects of surgical menopause on lipid levels and psychosocial characteristics: the Healthy Women Study. Health Psychol. 1995;14:435-443.
52. Avis NE, Brambilla D, McKinlay SM, et al. A longitudinal analysis of the association between menopause and depression. Results from the Massachusetts Women's Health Study. Ann Epidemiol. 1994;4:214-220.
53. Kessler RC, McGonagle KA, Swartz M, et al. Sex and depression in the National Comorbidity Survey I: lifetime prevalence, chronicity and recurrence. J Affect Disord. 1993;29:85-96.
54. Busch CM, Zonderman AB, Costa PT Jr. Menopausal transition and psychological distress in a nationally representative sample: is menopause associated with psychological distress? J Aging Health. 1994;6:209-228.
55. Dennerstein L, Smith AM, Morse C. Psychological well-being, mid-life and the menopause. Maturitas. 1994;20:1-11.
56. Mitchell ES, Woods NF. Symptom experiences of midlife women: observations from the Seattle midlife women's health study. Maturitas. 1996;25:1-10.
57. Van Hall EV, Verdel M, Van Der Velden J. "Perimenopausal" complaints in women and men: a comparative study. J Women's Health. 1994;3:45-49.
58. Campbell S, Whitehead M. Estrogen therapy and the menopausal syndrome. Clin Obstet Gynecol. 1977;4:31-47.
59. Morse CA, Smith A, Dennerstein L, et al. The treatment-seeking woman at menopause. Maturitas. 1994;18:161-173.
60. Kuh DL, Wadsorth M, Hardy R. Women's health in midlife: the influence of the menopause, social factors and health in earlier life. Br J Obstet Gynaecol. 1997;104:923-933.
61. Wiklund I, Karlberg J, Mattsson LA. Quality of life of postmenopausal women on a regimen of transdermal estradiol therapy: a double-blind placebo-controlled study. Am J Obstet Gynecol. 1993;168:824-830.
62. Daly E, Gray A, Barlow D, et al. Measuring the impact of menopausal symptoms on quality of life. Br Med J. 1993;307:836-840.
63. Woodward S, Freedman RR. The thermoregulatory effects of menopausal hot flashes on sleep. Sleep. 1994;17:497-501.
64. Schiff I, Regestein Q, Tulchinsky D, et al. Effects of estrogens on sleep and psychological state of hypogonadal women. JAMA. 1979;242:2405-2407.
65. Polo-Kantola P, Erkkola R, Helenius H, et al. When does estrogen replacement therapy improve sleep quality? Am J Obstet Gynecol. 1998;178:1002-10 09.
66. Dennerstein L, Burrows GD, Hyman GJ, et al. Hormone therapy and affect. Maturitas. 1979;1:247-254.
67. Sherwin BB. Affective changes with estrogen and androgen replacement therapy in surgically menopausal women. J Affect Disord. 1988;14:177-187.
68. Palinkas LA, Barrett-Connor E. Estrogen use and depressive symptoms in postmenopausal women. Obstet Gynecol. 1992;80:30-36.
69. Limouzin-Lamothe MA, Mairon N, Joyce CR, et al. Quality of life after the menopause: influence of hormonal replacement therapy. Am J Obstet Gynecol. 1994; 170:618-624.
70. Barrett DH, Anda RF, Escobedo LG, et al. Trends in oral contraceptive use and cigarette smoking. Arch Fam Med. 1994;3:438-443.
71. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre case-control study. Lancet. 1996;348:498-505.
72. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. Lancet. 1997;349:1202-1209.
73. Kirkman RJ, Pedersen JH, Fioretti P, et al. Clinical comparison of two low-dose oral contraceptives, Minulet and Mercilon, in women over 30 years of age. Contraception. 1994;49:33-46.
74. Fioretti P, Fruzzetti F, Navalesi R, et al. Clinical and metabolic study of a new pill containing 20 mcg ethinyl estradiol plus 0.150 mg desogestrel. Contraception. 1987;35:229-243.
75. Steffensen K. Evaluation of an oral contraceptive containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol in women aged 30 years or older. Acta Obstet Gynecol Scand Suppl. 1987;144:23.
76. Melis GB, Fruzzetti F, Nicoletti I, et al. A comparative study on the effects of a monophasic pill containing desogestrel plus 20 mcg ethinyl estradiol, a triphasic combination containing levonorgestel and a monophasic combination containing gestodene on coagulatory factors. Contraception. 1991;43:23-31.
77. Gordon EM, Williams SR, Frenchek B, Mazur CH, Speroff L. Dose-dependent effects of postmenopausal estrogen/progestin on antithrombin III and factor XII. J Lab Clin Med. 1988;111:52-56.
78. Basdevant A, Conard J, Pelissier C, et al. Hemostatic and metabolic effects of lowering the ethinyl-estradiol dose from 30 mcg to 20 mcg in oral contraceptives containing desogestrel. Contraception. 1993;48:193-204.
79. Fruzzetti F, Ricci C, Fioretti P. Haemostasis profile in smoking and nonsmoking women taking low-dose oral contraceptives. Contraception. 1994;49:579-592.
80. Castracane VD, Gimpel T, Goldzieher JW. When is it safe to switch from oral contraceptives to hormonal replacement therapy? Contraception. 1995;52:371-376.
81. Creinin MD. Laboratory criteria for menopause in women using oral contraceptives. Fertil Steril. 1996;66:101-104.
82. Gross TP, Schlesselman JJ. The estimated effect of oral contraceptive use on the cumulative risk of epithelial ovarian cancer. Obstet Gynecol. 1994;83:419-424.
Leon Speroff. Cover Story: Management of the perimenopausal transition. Contemporary Ob/Gyn 2000;10:14-37.