Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki-city, Osaka , Japan. Pituitary gonadotropin, Clinical managament

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1 Original Article Adequate Reduction Degree of Pituitary Gonadotropin Level in the Clinical Management of Short-Term Hormone Replacement Therapy of Women with Menopausal Symptoms Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki-city, Osaka 59-, Japan Key Words Climacterium, Menopausal symptoms, Hormone replacement therapy, Pituitary gonadotropin, Clinical managament ABSTRACT The purpose of this study was to clarify the adequate reduction rate of pituitary gonadotropins in ideal clinical management of short-term hormone replacement therapy (ST-HRT) in postmenopausal women with undefined symptoms. Subjects included a total 3 postmenopausal patients between and 1 years of age who visited the Department of Obstetrics and Gynecology at Osaka Medical College Hospital for the consult of menopausal symptoms. Subjects received oral administration of conjugated equine estrogen (0.5 mg/day) and progestin (.5 mg/day) for weeks as conventional HRT. HRT was markedly effective in.7% of cases, effective in 0.7%, fairly effective in 1.9%, and ineffective in.% of cases. The plasma concentration of follicle stimulating hormone (FSH) and luteinizing hormone (LH) after administration decreased significantly (P 0.001) by 5.1% and 59.9% for markedly effective cases, and by 31.0% and 3.1% for effective cases. On the other hand, decrease in FSH and LH concentration were 1.1% and 1.3% for the fairly effective and.5% and -5.1% for ineffective cases, demonstrating a significantly greater decrease in plasma FSH and LH levels in the markedly effective and effective cases than those in ineffective cases (P 0.001). There were significant differences in the reduction rates of plasma FSH and LH levels between in cases showing (59.9% and 53.%) and not showing the adverse effects (.% and 5.9%), respectively (P ). In conclusion, efficacy of ST-HRT was significantly correlated to the degree of decrease in plasma FSH and LH levels in patients with undefined symptoms. In addition, efficacy appeared to be correlated to the incidence of side effects. The degree of reduction of FSH (.-31.0%) and LH ( %) from the baseline may possibly be used as the suitable therapeutic window for hormone levels during HRT. The present results suggest that plasma gonadotropin levels could be a useful indicator for the management of patients undergoing short-term HRT for women with menopausal symptoms. Address correspondence to: Takahisa Ushiroyama, M.D., Ph.D. Department of Obstetrics and Gynecology, Osaka Medical College, -7 Daigaku-machi, Takatsuki, Osaka 59-, Japan gyn003@poh.osaka-med.ac.jp Fax: Phone: (ext. 91)

2 9 INTRODUCTION Menopausal symptom such as hot flashes is a common and major problem for women in the years preceding and following the final spontaneous menstruation or surgical oophorectomy; referred to as the peri- and postmenopausal years (UPTON, 190; BOULET et al, 199). Such women require estrogen treatment for relief of symptoms. Timely estrogen replacement or oral contraceptive use are considered to be effective in reducing bone mineral loss (LINDSAY, 197; KLEEREKOPER et al, 1991) and for providing protection from cardiovascular disease (STAMPFER, et al, 195; STAMPER et al, 1991). Recently, the Women s Health Initiative designed the first randomized trial study for.5 years to directly address whether estrogen plus progestin had a favorable or unfavorable effects on cardiovascular heart disease (CHD) incidence and on overall risks and benefits in 1,0 predominantly healthy women (WHI Investigators, 00). They reported that the rate of women experiencing CHD events, invasive breast cancer, and venous thromboembolic disease were increased by 9%, %, and 111% for women taking estrogen plus progestin relative to placebo, respectively. The trial was stopped early based on health risks that exceeded health benefits over an average follow-up of 5. years. These results indicate that hormone replacement therapy (HRT) regimen of combined estrogen with progestin should not be initiated or continued for primary prevention of CHD. After this report, criticism against HRT intensified, and the number of clinicians who avoid the use of HRT to prevent diseases induced by estrogen deficiency has been increasing. However, since the effectiveness of HRT as a means of treating menopausal symptoms has been established and because criticism against short-term HRT has not been made, consensus is being reached on the view that HRT should be used as a means of alleviating symptoms rather than as a means of preventing diseases. While estrogen replacement improves the wellbeing and physical activity of postmenopausal women, genital bleeding during hormone replacement therapy is one of the major reasons for discontinuing treatment. Furthermore, concomitant use of progestin has been recommended to reduce the risk of endometrial hyperplasia or endometrial cancer. However, the occurrence of adverse effects due to the addition of progestin, as well as genital bleeding, remain problematic. Estrogen appears to be effective in controlling the symptoms of menopause, including hot flashes, insomnia, vaginal dryness. The present paper documents the effects of short-term hormone replacement therapy on the reduction of undefined symptoms during menopause. Changes in plasma gonadotropins were monitored throughout treatment. The correlation between the clinical effects of shortterm hormone replacement therapy and changes in plasma gonadotropins was also investigated. MATERIALS and METHODS Patients Subjects were 3 postmenopausal women treated with hormone replacement therapy with undefined symptoms were recruited from the outpatient gynecology clinic of Osaka Medical College Hospital, School of Medicine. Spontaneous menopause was determined to have occurred if there had been no menstruation in the previous 1 months. Menopausal status was also confirmed by detection of postmenopausal levels of plasma FSH, LH and estradiol concentration: an FSH of at least 30 miu/ml, LH of at least 15 miu/ml and estradiol of below 10 pg/ml. None of the patients had a history of prior use of menopausal HRT. Protocol Patients with undefined symptoms underwent hormone replacement therapy (conjugated equine estrogen (CEE) 0.5 mg and medroxyprogesterone acetate (MPA).5 mg daily, continuous administration regimen) for weeks. All subjects gave informed consent of their willingness to participate in the study. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Clinical evaluations were performed at the start of treatment (baseline) and after, and weeks of treatment. The intensity of the following symptoms was graded at the baseline: hot flashes, general fatigue, insomnia, depressive mood or anxiety, headache, dizziness, palpitations, muscular problems (shoulder stiffness, cramps, weakness), abdominal fullness or discomfort and physical aches. Points for intensity were assigned to each symptom: severe (3 points), moderate ( points), slight (1 point) or not present (0 point). The same evaluation was repeated after, and weeks. An improvement in symptoms was said to have occurred when the score was half the initial score. Markedly

3 adequate clinical management of hormone replacement therapy 70 effective, effective and fairly effective cases were defined as improvement within, and weeks of treatment, respectively. We also evaluated clinical symptoms with Standard Climacteric Scale by Greene (GREENE, 199). Hormonal assays Plasma FSH and LH concentrations were measured using commercially available EIA kit (Nissui Kagaku, Co. Ltd., Japan). The limit of detectability of the assay was 0. miu/ml for FSH and 0.3 miu/ml for LH. The intra- and interassay coefficients of variation were.0% and 9.%, respectively, for FSH, and 11.0% and 1.1%, respectively, for LH. Estradiol was measured using a commercially available RIA kit (Estradiol Direct Kit, Sorin Biomedica, France). The limit of detectability of the assay was 3 pg/ml, and the intra- and interassay coefficients of variation were.0% and 9.5%, respectively. The cross-reactivity of estrone in the estradiol RIA kit was less than 0.7%. Data Analysis Statistical analysis was performed using Wilcoxon-Mann-Whitney tests to evaluate differences in plasma hormone levels. P values less than 0.05 were considered significant. RESULTS Table 1 presents the clinical characteristics of the 3 postmenopausal subjects. Age, age at menopause, months since the menopause, body mass index, baseline FSH, LH and estradiol levels and baseline symptoms are summarized. The combined administration of CEE and MPA was markedly effective in.7% (93 / 3) of Table 1. Baseline characteristics of the subjects Characteristics Age (years) Age at menopause (years) Months since the menopause (months) Body mass index (kg/ ) Baseline hormone levels FSH (miu/ml) LH (miu/ml) estradiol (pg/ml) Incidence of baseline symptoms (%) (high frequent 10 symptoms in the subjects) hot flush dizziness shoulder stiffness fatigue sweating joint pain depressed mood, irritation insomnia headache physical dysphoric feeling *: involving overlap symptom Mean SD n= * Table. Assessment of the efficacy of HRT with number of days needed for improvement in ill-defined symptoms and changes of plasma gonadotropins and estradiol. Days needed for improvement in symptoms n % Plasma hormone concentration FSH (miu/ml) LH (miu/ml) Estradiol (pg/ml) Within weeks 93 / 3.7 Within weeks 13 / Within weeks 71 / No change /

4 71 cases, effective in 0.7% (13 / 3) and fairly effective in 1.9% (71 / 3). In.% ( / 3) of cases, the points score had not decreased to less than half of the initial value by weeks of treatment (Table ). The plasma concentration of FSH and LH after administration decreased significantly (P 0.001) by 5.1% (.5 1. nmiu/ml) and 59.9% (1.1. miu/ml) for markedly effective cases, and by 31.0% (7.0(1.9 miu/ml) and 3.1% (. 9. miu/ml) for effective cases. On the other hand, decreases in FSH and LH concentration were 1.1% ( miu/ml) and 1.3% ( miu/ml) for the fairly effective and.5% ( miu/ml) and 5.1% ( miu/ml) for ineffective cases, demonstrating a significantly greater decrease in plasma FSH and LH levels in the markedly effective and effective cases than those in ineffective cases (P 0.001). In mean plasma estradiol level, patients showed significantly increase in markedly effective cases (1. fold from baseline: pg/ml) and effective cases (1.1 fold from baseline: 70.. pg/ml) (P ). We also observed significantly increases in the fairly effective (9.0 fold from baseline: pg/ml) (P ) and the ineffective cases (5.1 fold from baseline: pg/ml) (P 0.001) Table 3 presents side effects of the hormone replacement therapy in the subjects. During the treatment, 17 / 3 (39.%) experienced side effects. The undesirable side effects composed of uterine bleeding (9.0%: 9 / 3), breast pain and discomfort (9.%: 31 / 3), edema (.0%: / 3), and abnormal skin feeling (5.%: 1 / 3). There were significant differences in the reduction Table 3. Side effects of hormone replacement therapy with HRT in postmenoapusal women Symptoms Uterine bleeding Breast pain, discomfort Edema Abnormal skin feeling Headache Nausea, vomiting Sense of abdominal fullness Elevation of liver transaminase Palpitations Decreased urine volume Overall incidence n % 9 / / 3 9. / / / 3 3. / 3.5 / / 3 0. / / / Table. Comparison of changes in plasma FSH, LH and estradiol levels during weeks of treatment with HRT between women who did and did not experience side effects Treatment weeks Reduction or elevation rate from initial levels with side effects without side effects n=17 n=197 Statistical difference FSH LH Estradiol % % 5..% % % % % % 5.1. fold fold 9.5. fold 1.7. fold % % %. 0.% 9..3% % % %. 1.1 fold fold. 5. fold fold

5 adequate clinical management of hormone replacement therapy 7 degree of plasma FSH and LH levels in the weeks treatment with HRT between in cases experienced ( % and %) and not experienced side effects (. 0.% and %), respectively (P 0.001) (Table ). The mean plasma FSH, LH and estradiol levels were analyzed in relation to the type of side effects (uterine bleeding, edema, breast pain or discomfort, and abnormal skin feeling) occurring during weeks after the start of treatment (Table 5). At week-, the mean plasma FSH level decreased to.9 5. miu/ml for patients who developed uterine bleeding (n = 9) and miu/ml for patients who developed edema (n = ), which was 3.% and 3.1% of the pretreatment level, respectively. The mean plasma LH level at treatment week- decreased to miu/ml for patients who developed uterine bleeding and miu/ml for patients who developed edema, which was 1.7% and.3% of the pre-treatment level, respectively. The mean FSH levels for these two groups was significantly lower than that for patients who developed abnormal skin feeling (3. 1.5mIU/ml, n = 1) (P 0.05). The plasma estradiol level for patients who developed uterine bleeding (. 0. pg/ml) was significantly higher than that for patients who developed abnormal skin feeling ( pg/ml) (P 0.05). There were significant differences in the reduction degree of plasma FSH and LH levels in the weeks treatment with HRT between in cases experienced ( % and %) and not experienced uterine bleeding ( % and 3.0.%), respectively (P 0.001) (Table ). Of the 9 patients who developed uterine bleeding, 7 (7.%) showed a reduction in both plasma FSH and LH levels to the levels equivalent to those seen in individuals during sexual maturation. Table 5. Comparison of plasma FSH, LH and estradiol levels during weeks of treatment with HRT in women who experienced different side effects Side effects n FSH (miu/ml) LH (miu/ml) Estradiol (pg/ml) Uterine bleeding Edema Breast pain, discomfort Abnormal skin feeling *: P * * * Table. Comparison of changes in plasma FSH, LH and estradiol levels during weeks of treatment with HRT between women who did and did not experience uterine bleeding Treatment weeks Reduction or elevation rate from initial levels with uterine bleeding without uterine bleeding n=9 n=30 Statistical difference FSH LH Estradiol % % 57..% % % %. 9.5% % 7.3. fold fold fold fold % % % % 1.1.3% % % 3.0.% fold fold.1 5. fold. 5.5 fold

6 73 DISCUSSION Undefined symptoms such as hot flashes are among the primary reasons for women who are approaching the menopausal and postmenopausal years to seek medical attention. Since the efficacy of a continuous estrogen ( mg conjugated equine estrogen) -progestin (.5 mg medroxyprogesterone acetate) regimen has been recommended as the primary HRT for postmenopausal patients (WEINSTEIN, 197), this regimen has been used as the standard method of HRT for the past decade. However, a concern for both physicians and patients is that higher doses of estrogen could precipitate additional estrogenrelated side effects and increase the risk of and breast cancer. The publication of two large randomized clinical trials the Heart and Estrogen / progestin Replacement Study (HERS) and the Women s Health Initiative (WHI) of continuous-combined estrogen-progestin therapy (HRT) for postmenopausal women (WHI INVESTIGATORS, 00; HULLY et al, 199) have been reported as providing new and shocking information on HRT. These two major studies have put postmenopausal hormone replacement therapy as preventive strategy into a new perspective. Especially, in the wake of the publication of WHI results (WHI INVESTIGATORS, 00), numerous comments and position statements were issued, most of which endorsed the conclusions of the WHI researchers: in essence, this would limit the prescribing of hormone therapy to symptomatic menopausal women, for a period of -5 years (NOTELOVITZ, 003). A questionnaire survey, conducted of 1 middle-aged and elderly women in Japan months after WHI-HRT publication, yielded the following findings (USHIROYAMA et al, 003). It was shown that HRT was understood as a treatment of menopausal disorders at the highest rate (31.%) among HRT non-users, but was also understood as a treatment of osteoporosis (17.5%) and a treatment for prevention of dementia (1.%). Only.% of the respondents answered that HRT is a means of primary prevention of CHD. In view of the level of awareness of Japanese women about HRT, we may say that also in Japan, like in many other countries in the world, HRT should not be administered as a means of preventing osteoporosis and CHD but its use should be confined to short-term treatment of symptomatic menopausal women. Under such circumstances, we performed short-term HRT in postmenopausal women complaining of menopausal symptoms to achieve ideal outpatient management in terms of efficacy and side effects, using plasma gonadotropin and estradiol levels as indicators. Recently, we demonstrated that estriol was shown to be effective in approximately 7%, 7%, 5%, and 0% of women who complained of hot flashes, general fatigue, palpitations, and muscular problems, respectively, in postmenopausal period (USHIROYAMA et al, 001), and the significant relationship between efficacy and the reduction degree of gonadotropins, whereas the estradiol level remained 5 pg/ml despite receiving estriol mg daily. We supposed that the reduction degree of FSH ( %) and LH (.0-.3%) could be used as the suitable therapeutic window for hormone levels during estrogen replacement with estriol for undefined symptoms in postmenopausal women. In this study we observed that significantly greater decrease in plasma FSH and LH levels, and increase in plasma estradiol level in the markedly effective and effective cases than those in ineffective cases. Furthermore, significant differences in the reduction degree of plasma FSH and LH levels between in cases experienced and not experienced side effects. Adverse effects occurred in 39.% (17 / 3) of all cases. The major adverse effects were uterine bleeding (9.0%) and breast pain (9.%). During the past decade, a number of different estrogens and progestins at different doses have been tested in order to find the ideal combination. In spite of various dose combinations being tested, most investigators have reported a relatively high incidence of uterine bleeding (0-57% of patients) during the 3- months of treatment (MATTSSON et al, 19; WEINSTEIN et al, 1990; HARGROVE et al, 199). Uterine bleeding, breast pain and discomfort are very uncomfortable for patients. Plasma FSH and LH levels decreased more greatly in patients who developed uterine bleeding or edema. Percent increase in plasma estradiol level was also greater in patients who developed uterine bleeding. To reduce the dropout rate and enhance compliance, these adverse effects should be suppressed as much as possible. Recently, the concept of physiological HRT with transdermal estrogen preparations has been introduced for long-term HRT to deal with postmenopausal estrogen deficiency. DUPONT et al. reported that the plasma estradiol level was approximately 0-00 pg/ml and the E1/E ratio was 5-7 after conjugated equine estrogen therapy alone, but

7 adequate clinical management of hormone replacement therapy 7 that the E1/E ratio was approximately 1 after transdermal estrogen therapy. Based on these results, DUPONT et al. (1990) concluded that the E1/E ratio close to the physiological E1/E ratio seen before menopause could be achieved by transdermal estrogen therapy. Concerning the uterine bleeding, a side effect, it is known that an increase in the percentage of progestin contained in HRT preparations elevates the incidence of endometrial atrophy. High doses of progestin can also adversely affect the metabolism of serum lipoprotein. Therefore, adjustment of the dose level for individual patients is essential (DARJ et al, 1991; SIDDLE et al, 191; OTTOSSON et al, 195). Plasma gonadotropin level will serve as a valuable indicator when making such adjustment. Thus, the plasma concentration of FSH and LH may be important in the management of HRT. According to present results, it is observed that higher reduction of plasma FSH and LH levels by the HRT induce not only higher clinical efficacy but higher incidence of side effects. The degree of reduction of FSH (.-31.0%) and LH ( %) from the baseline may possibly be used as the suitable therapeutic window for hormone levels during HRT. Though HRT is expected to exert high efficacy in the actual clinical practice, it is desirable to avoid a high incidence of adverse effects as far as possible. In cases where the therapy was rated as showing reliable efficacy although the response was not rated as complete responses, the mean percent reduction in FSH and LH was 31.0% and 3.1%, respectively. If the percent reduction in FSH and LH becomes higher than these levels, the number of cases showing CR will increase, but adverse effects will be more likely to appear. Inversely, if the percent reduction in FSH and LH is lower than these levels, the efficacy will be lower, but side effects are less likely. Because the mean reduction in FSH and LH was.% and 5.9% in cases free of side effects, we may say that if the goal of the amount of reduction is set at.-31.0% for FSH and % for LH, reliable clinical efficacy with minimal side effects is expected although CR is unlikely to be achieved. It is proper that clinical managements tailored to individual case are needed, but setting these clinical indicator will be contribute as a therapeutic window of pituitary gonadotropin level. Uterine bleeding is one of the most significant adverse effects of HRT. In patients showing uterine bleeding, the plasma FSH level decreased to about half after weeks of HRT, and the percent reduction in FSH after only weeks of HRT was about 0% greater than that in patients free of uterine bleeding (P 0.001). We therefore considered that a large reduction in FSH in early stages of HRT could elevate the incidence of uterine bleeding as an adverse reaction. If the plasma FSH level has decreased by 0-50% during the first weeks of HRT, it is considered that sufficient management and care are needed in continuing the therapy. A similar trend was also noted in the change in plasma LH level, but the difference between patients showing and free of uterine bleeding was smaller for plasma LH level than for plasma FSH level. After weeks of HRT, percent reduction in plasma FSH and LH level was 3.% and 5.1% respectively, in cases showing uterine bleeding as an adverse reaction. To minimize the onset of uterine bleeding as an adverse reaction to HRT, it is advisable to keep percent reduction in plasma FSH and LH levels smaller than the mean percent reduction seen in patients free of uterine bleeding (reduction by % for FSH and 3.0.% for LH). In other words, we may say that the incidence of uterine bleeding as an adverse reaction to HRT becomes higher if percent reduction in FSH or LH level exceeds the mean percent reduction. If the percent reduction is kept below the mean - 1SD (5.1% for FSH and 35.3% for LH), the incidence of uterine bleeding will be considerably low. Therefore, taken together, the present results suggest that a reduction of approximately less than 0% and 35% from initial FSH and LH levels, respectively, may be the optimal value for a suppression of uterine bleeding during HRT. Percent increase in plasma estradiol level may also be adopted as a therapeutic window, but the SD of this parameter in our data was too large to allow us setting a reliable indicator of percent increase in plasma estradiol level. We may say that time has come to review the indications of HRT when dealing with estrogen deficiency-induced conditions during the postmenopausal period. Under such circumstances, it is necessary to establish further strategies for short-term treatment of symptomatic menopausal women. The results obtained in the present study suggest that patient management based on periodical measurement of blood hormone levels is essential to elevate drug compliance with the goals of maximizing the clinical efficacy of HRT and minimizing side effects to this therapy.

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