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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 5 2026-2030
Copyright © 2003 by The Endocrine Society

Increase of Estrogen Dose Deteriorates Mood during Progestin Phase in Sequential Hormonal Therapy

Inger Björn, Inger Sundström-Poromaa, Marie Bixo, Sigrid Nyberg, Gunnel Bäckström and Torbjörn Bäckström

Department of Clinical Science, Obstetrics and Gynecology, University Hospital of Umeå, 90185 Umeå, Sweden

Address all correspondence and requests for reprints to: Dr. Inger Björn, Läkarhuset Björnen, Lillbrogatan 8, S-941 32 Piteå, Sweden. E-mail: inger.bjorn{at}telia.com.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Previous studies have indicated that the addition of progestins during sequential hormonal replacement therapy (HRT) causes negative mood and physical symptoms. History of premenstrual syndrome, type of progestin, and dose of progestin have thus far been shown to influence the progestin-induced adverse mood symptoms during HRT.

The aim of this study was to compare adverse mood effects of two different doses of estradiol, in combination with a progestin, during postmenopausal HRT. Twenty-eight perimenopausal women were included in this randomized, double-blind, crossover study comparing 2- or 3-mg continuous estradiol, with an addition of 10 mg medroxyprogesterone acetate on d 17–28 during each treatment cycle. The main outcome measures were mood and physical symptoms kept on a daily rating scale. Together with the progestin, the higher dose of estrogen caused significantly more negative mood symptoms than the lower dose. Tension, irritability, and depressed mood were all significantly augmented during the progestin phase of cycles with 3 mg estradiol (P < 0.001). Physical symptoms also increased during the progestin phase of 3-mg estradiol cycles (P < 0.001), whereas positive mood symptoms were less affected. The only positive mood that changed with estrogen dose was friendliness, which decreased during the progestin phase of high estradiol cycles compared with cycles with lower estradiol (P < 0.05).

Our conclusion is that an increase of the estrogen dose accentuates negative mood and physical symptoms during the progestin phase of sequential hormonal therapy.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
WHEREAS ONSET OF menopause seems not to be associated with an increased risk of clinical depression (1), estrogen treatment is known to enhance well-being and quality of life in women with climacteric complaints (2, 3, 4). In women with an intact uterus, estrogen treatment is always supplemented with progestins, to ensure endometrial protection. Progestins alone do not seem to provoke negative side effects in treatment of postmenopausal women (5), but in combination with estrogen, progestin-induced dysphoria has been reported consistently (6, 7, 8). In a meta-analysis by Zweifel and O’Brian (4), hormone replacement therapy (HRT) was effective in reducing depressed mood in a nondepressed healthy sample of menopausal women. However, progestin alone or in combination with estrogen was associated with smaller reductions in depressed mood than estrogen by itself (4). Likewise, women treated with estrogen and sequential progestin experienced more negative mood and more psychological symptomatology compared with women treated with a higher dose of unopposed estrogen (6). Klaiber et al. (9) found a relationship between increased dysphoria, long duration of menopause, and higher treatment serum estradiol levels in women receiving a combination of estrogen plus progestin.

We have in previous studies reported that the addition of progestins during sequential hormonal therapy increases negative mood and physical symptoms, and reduces positive mood symptoms (7). The type of progestin seems to be of importance, because medroxyprogesterone acetate (MPA) provoked less negative symptoms compared with noretisterone acetate. Furthermore, women who had a history of premenstrual syndrome (PMS) were more sensitive to progestins and responded with less positive mood effects than women who had not suffered from PMS. Finally, the dose of the progestin is also of interest. In sequential hormonal therapy, the addition of 20 mg MPA surprisingly provoked less negative mood symptoms compared with 10 mg, and in women with PMS history, 20 mg MPA even enhanced positive mood symptoms (8).

Adverse mood effects during sequential HRT have been compared with the symptoms experienced in the late luteal phase in women with PMS (10, 11), and studies on PMS might, therefore, be complementary to clinical trials in postmenopausal women. Women with PMS, treated with conjugated estrogen (CEE) during the luteal phase, respond with worsened symptomatology compared with those treated with placebo (12). The synergistic effect of estradiol and progesterone seems to be essential to induce premenstrual symptoms (13), and our previous studies have indicated that adverse mood symptoms during sequential HRT require treatment with both estradiol and a progestin (7, 8). The purpose of the present study was to investigate whether the dose of estrogen has an impact on adverse mood symptoms and physical symptoms in perimenopausal women during the progestin phase of sequential hormonal therapy. We hypothesized that during the progestin phase of cycles with the higher estradiol dose, adverse mood symptoms would be more pronounced than during cycles with a lower estradiol dose.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study was carried out in northern Sweden at three health centers in small towns with surrounding rural areas. It lasted from December 2000 until November 2001. Thirty-eight healthy women with climacteric symptoms were recruited for the study. The women were perimenopausal, had more than 6 months of amenorrhea, and serum FSH (s-FSH) levels greater than 18 IU/liter. They had used no other HRT for more than 3 months before inclusion of the study. They were not receiving any steroid treatment, had an intact uterus and ovaries, and had no contraindications toward HRT. The women did not have any history of psychiatric illness and had never been treated with psychopharmacological drugs. The presence of psychiatric disorders and drug abuse were evaluated using a structured psychiatric interview, Prime-MD, which has been validated for use in primary care settings and conforms to diagnostic criteria in Diagnostic and Statistical Manual of Mental Disorders, 4th edition (14). None of the patients were clinically depressed but 54% expressed negative mood due to climacteric symptoms (Table 1Go). The women gave written informed consent and agreed to keep a daily record of symptoms. Before taking part, the women underwent a physical and gynecological examination, including a transvaginal ultrasound, and blood sampling for s-FSH.


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  		Table 1. Demographic data of the study group (n = 28)

 
Study design

The effect of the two different estradiol doses on symptom cyclicity and severity was evaluated in a randomized, double-blind, crossover design. Before entering the different treatment arms, patients rated baseline mood scores for 28 d. Hereafter, estradiol in a dose of either 2 or 3 mg was given continuously for five 28-d cycles (one run-in cycle and four study cycles). The doses of estradiol chosen for the study were based on 2 mg being the golden standard in studies on HRT.

Ten milligrams of MPA were added on d 17–28 of each treatment cycle. Eligible patients were assigned to the two different estrogen doses in a sequence determined by a computerized random-number generator. One group started the sequential treatment with 2 mg estradiol and the other group with 3 mg estradiol. A crossover to the other dose of estradiol was carried out after three cycles, and the study continued for another two cycles. During the study, the subjects and study personnel were not informed about the order of treatments. Randomization codes were kept secret at the pharmacy at Umeå University Hospital until completion of the study. The medicines were prepared by Apoteksbolaget (the National Pharmacy Company), Production and Laboratories. The capsules were made to look identical and were packaged in 28-d blister cards by the pharmacy at Umeå University Hospital. The women were seen by a gynecologist three times during the study period: at inclusion, after 10 wk of treatment, and at termination of the study (24 wk). Weight, blood pressure, and s-FSH were followed up after 10 and 24 wk. Compliance was assessed by counting the remaining capsules at each visit. The primary outcome measure was the daily symptom ratings made by the women throughout the study. We used a modified form of the Cyclicity Diagnoser (CD) scale. The CD scale has been validated as an instrument designed for diagnosing cyclical symptoms (15). The modified CD scale included four physical symptoms (breast tenderness, hot flashes, abdominal bloating, and withdrawal bleeding) and seven psychological symptoms (cheerfulness, friendliness, libido, anxiety/tension, irritability, fatigue, and depressed mood). The effects on daily life caused by symptoms were graded. The CD scale is a Likert scale graded from 0 to 8, where 0 indicates complete absence of a particular symptom and 8 represents the maximum severity of the symptom. One scale step is enough to detect a difference in mood experience as indicated by a study on symptom severity in women with PMS (16). The Umeå University Ethical Committee and the National Medical Products Agency approved the design of the study.

Hormone assays

FSH concentrations were measured by microparticle enzyme immunoassay on AxSYM (Abbott Laboratories, Abbott Park, IL). The assay sensitivity was 0.37 IU/liter with intra- and interassay coefficients of variation being 3.5% and 2.3%, respectively.

Statistics

The first treatment cycle was not included in the analysis because it was used as a run-in cycle. Because estrogen is known to increase well-being during the first month of treatment, this cycle was excluded to avoid interference with mood effects due to reduction of vasomotor symptoms (17). Consequently, baseline mood scores and cycles 2–5 are included in the analyses. Symptoms were analyzed separately and in clusters of related symptoms. Related symptoms were grouped together as mean scores of summarized symptoms: "negative mood symptoms" (i.e. fatigue, tension, irritability, and depressed mood); "positive mood symptoms" (i.e. cheerfulness and friendliness); and "physical symptoms" (i.e. breast tenderness and bloating). The effects of the different doses of estrogen on each symptom and on summarized negative, positive, and physical symptoms were analyzed by two-way ANOVA with repeated measures. Factors in these analyses were cycle day and estrogen dose (2 mg vs. 3 mg). The Wilcoxon paired t test was used to compare levels of s-FSH before and during treatment. The SPSS statistical package (SPSS, Inc., Chicago, IL) was used for the analyses. A P value less than 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Of the 38 women included in the study, 28 completed all treatment cycles. Three patients were excluded because of the following reasons: one due to spontaneous bleeding during the nontreatment cycle, one due to an expired drug date, and one due to noncompliance with the study protocol (insufficient rating scales). Seven additional patients dropped out of the study for various reasons: four never started medication because of personal reasons, two because of negative side effects (bloating and edema), and one due to insufficient treatment effect. Demographic data of the study group are shown in Table 1Go.

Levels of FSH, blood pressure, and weight were monitored throughout the study course. All women had FSH levels above 35 IU/liter, except one. s-FSH decreased significantly from a mean value of 73 IU/liter (range, 23–147) to 24 IU/liter (range, 2.6–102) from the onset of the study until termination at 24 wk (P < 0.001). Blood pressure (mean, 126/80 mm Hg) and weight (mean, 73 kg) did not change throughout the study course.

Differences before and during treatment

The women scored presence of all symptoms, except bleeding during the baseline period. There was no cyclicity in mood or physical symptoms during this 1-month period before treatment. Compared with pretreatment ratings, hot flashes and irritability decreased significantly during sequential estrogen and progestin treatment (P < 0.001 and P < 0.05, respectively). Breast tenderness, on the other hand, increased during treatment (P < 0.05). All other symptoms were unaltered between the untreated and treated state.

Difference between 2 mg and 3 mg estradiol during the progestin phase of the treatment cycle

During the progestin phase, the higher dose of estrogen caused significantly more negative mood symptoms than the lower dose [F(1,27) = 19.35, P < 0.001]. Tension, irritability, and depressed mood were all significantly augmented during the progestin phase of cycles with 3 mg estradiol [tension: F(1,27) = 23.57, P < 0.001; irritability: F(1,27) = 19.54, P < 0.001; depressed mood: F(1,27) = 26.27, P < 0.001]. Symptom scores of libido and fatigue did not differ between estradiol doses [F(1,27) = 0.10 and F(1,27) = 0.01, respectively]. Summarized scores of negative mood symptoms during the different estradiol regimens are shown in Fig. 1Go. During 2-mg (but not 3-mg) estradiol cycles, the addition of progestin resulted in lower summarized negative mood scores than during the previous 12 days of estradiol-only therapy [estrogen dose by treatment phase, F(1,27) = 6.21; P < 0.05].



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  		Figure 1. Daily symptom ratings on a 9-point CD scale of summarized negative symptoms during sequential estrogen/progestin treatment. Each point represents the mean ± SEM of treatment cycles 2–5 among all women (n = 28). During the progestin phase (d 17–28), the higher dose of estrogen caused significantly more negative mood symptoms than the lower dose [F(1,27) = 19.35, P < 0.001].

 
Physical symptoms also increased during the progestin phase of 3-mg estradiol cycles [F(1,27) = 51.41, P < 0.001; Fig. 2Go]. Increased breast tension was the most pronounced physical change [F(1,27) = 84.32, P < 0.001] but, surprisingly, hot flashes were also more prominent during the progestin phase of 3-mg estradiol cycles compared with 2-mg cycles [F(1,27) = 5.92, P < 0.05].



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  		Figure 2. Daily symptom ratings on a 9-point CD scale of summarized physical symptoms during sequential estrogen/progestin treatment. Each point represent the mean ± SEM of treatment cycles 2–5 among all women (n = 28). Physical symptoms increased during the progestin phase (d 17–28) of 3-mg estradiol cycles compared with 2-mg cycles [F(1,27) = 51.41, P < 0.001].

 
Positive mood symptoms were less affected. The only positive mood symptom that changed with estrogen dose was friendliness, which decreased during the progestin phase of high estradiol cycles compared with cycles with lower estradiol [F(1,27) = 5.91, P < 0.05].

Negative effect on daily life increased during the progestin phase of 3-mg estradiol cycles compared with 2-mg cycles [F(1,27) = 11.40, P < 0.001].


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The major finding of the present study is that women, during the progestin phase of HRT, experienced more pronounced negative mood symptoms such as irritability, tension, and depressed mood if the estrogen dose was 3 mg instead of 2 mg. In addition, breast tenderness and hot flashes increased with the higher estrogen dose in combination with the progestin. This is, to our knowledge, the first time that estrogen, when combined with a progestin, has been shown to have a dose-dependent effect on mood deterioration. At first sight, progestins appear to be the major contributor to the adverse mood effects seen during the progestin phase of HRT, but our results clearly indicate that increased estrogen doses, in combination with a progestin, has the ability to deteriorate mood symptoms. Given the present findings, it is, thus, likely that the combination of estrogen and progestins contribute to the overall effect on mood. Other studies support this finding. For instance, if medroxyprogesterone is given on its own to postmenopausal women, the compound seems not to have any adverse effects on mood (5). However, when a progestin is sequentially combined with estrogen, PMS-like symptoms are provoked (10, 11). Also, the usefulness of estrogen as treatment for premenstrual symptoms has been evaluated, and instead of the expected positive treatment effect, it was concluded that estrogen worsened the symptomatology during the luteal phase (12).

Very little is known about the impact of the dose of estrogen and mood symptoms during postmenopausal hormonal therapy. Sherwin (6) found that 1.25 mg CEE and placebo were more beneficial regarding mood and physical symptoms than 0.625 mg CEE and sequential MPA in a 1-year study on 48 healthy, naturally menopausal women. The addition of 5 mg MPA to either 0.625 mg or 1.25 mg CEE attenuated the beneficial effects of estrogen on emotional well-being in a dose-dependent manner. It was suggested that a higher estrogen to progestogen ratio would cause fewer psychological symptoms in women on combined replacement regimens, which is at odds with our findings. This study, however, included four treatment arms, and no crossover to another treatment regimen was made, which is why direct comparisons cannot be made. It seems obvious, however, that the effects on mood induced by estrogen and progestins given separately are different compared with when they are combined.

At odds with our previous studies, the present findings indicated that the progestin addition to 2 mg estradiol had a beneficial effect on negative mood. We and others have previously reported that the addition of a progestin during estrogen treatment has negative effect on mood, hot flashes, bloating, and breast tenderness (7, 8, 10, 17, 18, 19, 20). Kirkham et al. (21) found no adverse effects of the addition of 10 mg MPA to transdermal estrogen in hysterectomized and ooforectomized women, but the study lasted for only one treatment cycle. The most likely reason for discrepancies between the current and prior studies is the use of MPA instead of 19-nor-testosterone-derived progestins. We have previously shown that noretisterone acetate provokes more negative mood symptoms compared with MPA in healthy controls (7).

Compared with pretreatment ratings, hot flashes and irritability scores decreased during HRT. This is in concordance with earlier studies on well-being and mood during unopposed estrogen treatment in healthy clinical samples (3, 6). However, the effect of estrogen on clinical depression is thus far not established, even though some studies have indicated a possible antidepressive effect of estrogen (4, 22). On the contrary, there is strong support for the assumption that depressed mood during the perimenopause can be explained by severity of hot flashes and sleeping disturbances (23). Women without vasomotor symptoms are not improved by estrogen treatment in terms of well-being (24). We have shown in previous studies that treatment of hot flashes is efficient during estrogen-phase only (7, 8) but hot flashes increase when a progestin is added. In this study, we, surprisingly, found that an increased estrogen dose during the progestin phase worsened hot flashes compared with when a lower estrogen dose was used. This finding, however, remains to be verified by other studies.

There are two potential biases to the study findings. First, the women included were more than 6, instead of 12, months postmenopausal and can, therefore, be considered to be perimenopausal. It is known that the levels of serum estradiol decrease by 50% in women who are 3 months postmenopausal, but the levels still fluctuate and are higher compared with women with 12 months of amenorrhea (25). Levels of serum estradiol were not measured throughout the study course. Consequently, we cannot exclude the possibility that changes in endogenous estradiol might influence the results. The main outcome in our study was, however, the dose response of estrogen during the progestin phase and adverse mood effects. In addition, the treatment was given in a randomized order and should, thus, not be influenced by a gradual decrease in the endogenous production. Second, the estradiol- and progestin-induced changes in mood were studied over a 2-month period. We have previously reported that cyclical mood symptoms decline over a 4-month period (7) and, therefore, the results remain to be replicated by long-term studies.

The mood effects of estrogen and medroxyprogesterone are probably direct effects on neural function within the brain (26). The neuroendocrine effects of estrogen, progesterone, and their metabolites have been studied in various settings. Estrogen receptor {alpha} and ß and the progesterone receptor are expressed in brain areas known to be involved in mood, cognition, and memory, such as the hypothalamus, prefrontal cortex, hippocampus, and amygdala (26, 27). In addition, both 17ß-estradiol and some 5{alpha}/ß-reduced 3{alpha}-hydroxy metabolites of progesterone have effects on neural function via direct action on membrane-bound receptors (26). The serotonin system is of interest because serotonin re-uptake inhibitors are effective in treatment of the premenstrual dysphoric disorder (28) and because unopposed estrogen, as well as the combination of estrogen and progesterone, has the ability to modulate serotonin receptor expression. In the hippocampus of the female ovariectomized rat, long-term unopposed estradiol treatment had an opposite effect on 5-HT1A mRNA expression compared with estradiol supplemented with progesterone (29). Long-term unopposed estradiol decreases the 5-HT2A mRNA expression whereas estradiol in combination with progesterone increases the 5-HT2A mRNA expression in the ventral hippocampus in a region-specific manner (30). Furthermore, Wissink et al. (31) reported that estrogen up-regulates the expression of the 5-HT1A receptor via a nongenomic mechanism, involving nuclear factor-{kappa}B and estrogen receptor {alpha}. The glutamate system is also activated by estradiol via a direct nongenomic mechanism (32). Some metabolites of progesterone potently enhance GABAergic neurotransmission through interaction with the GABAA receptor. These progesterone metabolites are termed neurosteroids, and their involvement in affective disorders such as premenstrual dysphoric disorder, major depression, and panic disorder have recently begun to be elucidated (33, 34, 35). In the hippocampus, pretreatment with estradiol enhances the effect of the GABAA receptor-active progesterone metabolite allopregnanolone (36). Taken together, these findings are evidence of a direct effect of the ovarian steroids within the brain. However, the exact mechanisms underlying the results of the present study remain to be elucidated, and further speculation is beyond the scope of this publication. We conclude that an increase of the estrogen dose during sequential hormonal therapy accentuate negative mood symptoms during the phase of progestin addition. These findings may have an implication for the understanding the pathophysiology of progestin-induced dysphoria during HRT and possibly also for the understanding of premenstrual dysphoric disorder.


   Footnotes
 
This work was supported by The Swedish Society for Medical Research, The Swedish Research Council of Medicine (Project 4X-11198), Visare Norr and Samverkansnämnden Norra Regionen, Wallenberg Foundation, and EG-Regional Fund (Objective 1 Program).

Abbreviations: CEE, Conjugated estrogen; CD, Cyclicity Diagnoser; HRT, hormone replacement therapy; MPA, medroxyprogesterone acetate; PMS, premenstrual syndrome; s-FSH, serum FSH.

Received May 15, 2002.

Accepted February 6, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals