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  • Dtsch Arztebl Int
  • v.109(17); 2012 Apr
  • PMC3355503
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Dtsch Arztebl Int. 2012 Apr; 109(17): 316–324.
Published online 2012 Apr 27. doi:  [ 10.3238/arztebl.2012.0316 ]
PMCID: PMC3355503
PMID: 22611453
Continuing Medical Education

The Treatment of Climacteric Symptoms

Olaf Ortmann , Prof. Dr. med.*,1 and Claus Lattrich , Dr. med.1

Olaf Ortmann

1Department of Obstretics and Gynecology, University Medical Center Regensburg, Germany

Find articles by Olaf Ortmann

Claus Lattrich

1Department of Obstretics and Gynecology, University Medical Center Regensburg, Germany

Find articles by Claus Lattrich
Author information Article notes Copyright and License information Disclaimer
1Department of Obstretics and Gynecology, University Medical Center Regensburg, Germany
*Klinik für Frauenheilkunde und Geburtshilfe der, Universität Regensburg am Caritas-Krankenhaus St. Josef, Landshuter Str. 65, 93053 Regensburg, Germany, [email protected]
Received 2011 Aug 25; Accepted 2012 Mar 12.
Copyright notice
See letter ” Correspondence (letter to the editor): Do Not Forget Estrogen Therapy ” in volume 109 on page 714.
See commentary ” Correspondence (reply): In Reply ” in volume 109 on page 714.
This article has been cited by other articles in PMC.

Abstract

Background

Peri- and postmenopausal women commonly suffer from climacteric symptoms. In this article, we provide information to help physicians recognize climacteric symptoms and treat them appropriately.

Methods

The information presented here is based on a selective search of the literature for pertinent articles that appeared from 2008 to early 2011, including the German S3 guideline on hormone therapy (HT) during and after menopause, which was published in 2009.

Results

Perimenopausal women often suffer from climacteric symptoms. Typically, women undergoing menopause complain of heat waves and vaginal dryness. According to randomized controlled trials as well as national and international guidelines, HT is the most effective treatment for vasomotor symptoms and also improves vulvovaginal atrophy; for the latter indication, HT is preferably administered locally. Vaginal estrogen therapy lowers the frequency of recurrent urinary tract infections. However, HT is associated with an increased risk for a number of diseases, including stroke, thromboembolic events, gall-bladder diseases, and breast cancer. Alternative treatments for climacteric symptoms have little or no efficacy.

Conclusion

HT should only be used to treat climacteric symptoms after extensive patient education about its benefits and risks. Participatory decision-making is desirable. The generalized use of HT by all women with climacteric symptoms cannot be recommended.

Peri- and postmenopausal women often seek medical help, and climacteric symptoms are their most common reason for doing so. These symptoms are due to changes in ovarian function during the menopause. The transition from full ovarian function in the premenopausal period to a complete lack of ovarian estrogen synthesis in the postmenopausal period is, fundamentally, a normal aspect of human physiology, but specific disturbances or diseases may develop as a result of diminished estrogen synthesis. Moreover, the peri- and postmenopausal periods are marked by psychosocial and other age-related changes that can also cause certain physical symptoms. A rational approach to climacteric symptoms per se requires a well-founded knowledge of the specific physiological and pathophysiological changes affecting women at this time in their lives. A number of treatments are available; a commonly used one is peri- and postmenopausal hormone therapy (HT) with sex steroids. There has been a search for alternative treatments, particularly in recent years. In this review, we will discuss the main types of climacteric symptoms and their treatment. We will direct our attention primarily to HT, as it is clearly the most effective treatment available today.

Learning objectives

Readers of this article should gain knowledge of the following aspects of the treatment of climacteric symptoms:

  • the recognition of climacteric symptoms,
  • the effects of hormone therapy on them,
  • the risks of hormone therapy, and
  • alternative treatments.

Climacteric symptoms

There are a number of ways to treat climacteric symptoms. Hormone therapy with sex steroids is a common form of treatment in the peri- and postmenopausal periods.

Methods

This review is based on a selective search in PubMed for articles published from 2008 to 2011 that contained the key words “climacteric symptoms,” “menopausal symptoms,” “menopausal hormone therapy,” and “hormone replacement therapy.”

The retrieved publications are discussed in the text of this article if they contain information that is relevant to the topic of the article, as defined above. The state of scientific knowledge based on publications up to 2008 has already been taken into account in the creation of the German S3 guideline on hormone therapy (HT) in the peri- and postmenopausal periods ( 1 , 2 , e1 ).

This systematic search and assessment of scientific evidence was performed in relation to climacteric symptoms, quality of life, urogenital symptoms, the musculoskeletal apparatus, bone metabolism, cardiovascular diseases, other diseases and aging processes, CNS diseases, cancer, premature ovarian failure, and alternative treatments.

A detailed description of the manner of testing and assessing the scientific evidence can be found in the methods report accompanying the S3 guideline. The guideline contains position statements that were issued on the basis of an evaluation of the evidence followed by a consensus-building process. These statements, in turn, provided the basis for the clinical recommendations that were derived from them.

Consistently present climacteric symptoms

  • vasomotor symptoms (hot flashes, diaphoresis)
  • vaginal dryness

Climacteric symptoms and the quality of life

Perimenopausal women report so-called climacteric symptoms with varying frequency ( 1 – 3 , e1 ). Some of these are clearly attributable to the reduced synthesis of sex steroids (e.g., vasomotor symptoms), while others may be of multifactorial origin (e.g., mood fluctuations). The constellation of symptoms is often designated the climacteric syndrome; there is, however, no uniform definition of this syndrome. Many cohort studies and cross-sectional studies have been performed for the purpose of characterizing climacteric symptoms ( 4 – 8 , e2 , e3 ). The ones most consistently found were hot flashes and vaginal dryness. Further symptoms such as sleep disturbances, bodily symptoms of various kinds, urinary tract symptoms, sexual problems, and mood changes were less consistently present ( Box 1 ). The duration of hot flashes in relation to the beginning of menopause was the subject of a recently published cohort study of 436 initially premenopausal women aged 35 to 47. 90 of them developed mild hot flashes, while 259 developed moderate to severe hot flashes, and 55 had none at all. The mean duration of moderate to severe hot flashes was 10.2 years; they lasted particularly long (>11.57 years) if they had begun in the early perimenopausal period ( 3 ).

Box 1

Climacteric symptoms

  • Consistently appearing symptoms
    • vasomotor symptoms (hot flashes, diaphoresis)
    • vaginal dryness
  • Less consistently appearing symptoms
    • sleep disturbances
    • mood changes
    • urinary tract symptoms
    • sexual problems (loss of libido, dyspareunia, other)
    • other bodily symptoms

An overall assessment of the available studies provides no clear answer to the question whether women have a worse quality of life during this phase of their lives. The quality of life, however, was not uniformly defined from study to study, and women with and without vasomotor symptoms were included in the analysis. Clinical experience clearly shows that women who suffer from these symptoms to a major extent consider their quality of life to be markedly reduced. This is why they seek treatment.

Alternatives to hormone therapy

Because HT has certain risks, there has been a search for other treatments, particularly with drugs. Preparations of botanical origin are especially popular. There have been many trials on the treatment of climacteric symptoms with phyto-estrogens in the form of isoflavone from red clover or soya and Cimicifuga racemosa. Most of the placebo-controlled trials have failed to show any significant reduction of vasomotor symptoms ( 9 ), although some did reveal a small effect. Urogenital symptoms were not improved. In particular, nothing is known about the long-term safety of these preparations. For these reasons, phyto-estrogens and other botanical and non-hormonal alternatives to hormone therapy cannot be recommended.

Less consistent climacteric symptoms

  • sleep disturbances
  • mood changes
  • sexual problems
  • other bodily symptoms

A number of changes in lifestyle can, to some extent, improve mild vasomotor symptoms. This is suggested mainly by data from observational studies. Hot flashes can be reduced by low ambient temperatures. Women with a higher body-mass index were once thought to have less frequent hot flashes because of greater aromatization of androgens in adipose tissue, but recent studies have shown that they actually have more frequent hot flashes; thus, weight reduction down to a normal body weight is desirable. Non-smoking women suffer from hot flashes less commonly than smokers. Regular physical exercise, too, can improve hot flashes. Relaxation exercises have a beneficial effect on the frequency and intensity of hot flashes ( e4 ).

Women for whom hormone therapy is contraindicated, such as women with breast cancer, are in a special situation. The selective serotonin reuptake inhibitors venlafaxine and fluoxetine have been found effective against vasomotor symptoms; on the other hand, there is no clear evidence for the effectiveness of the antihypertensive agents clonidine and methyldopa in this context. Gabapentin, an anticonvulsant, has been found to have a beneficial effect on climacteric symptoms. The medications mentioned here as effective have not been approved for the treatment of climacteric symptoms. It would seem appropriate to use them off label, after sufficient patient education, in cases where hormone therapy is contraindicated ( 1 , 2 , e1 ).

Alternatives to hormone therapy

  • aiming for normal body weight
  • smoking cessation
  • regular physical exercise
  • relaxation exercises

Substances used for hormone therapy

In non-hysterectomized women, combined estrogen-gestagen therapy (EPT) must be administered instead of estrogen therapy alone (ET) in order not to elevate the risk of endometrial hyperplasia and endometrial carcinoma. Both oral and transdermal preparations of EPT are available ( Box 2 ); natural progesterone can also be administered vaginally. Either progesterone derivatives or norethisterone derivatives (C-21 or C-19 steroids, respectively) can be used; these may have different partial effects, and one or the other can be chosen for use accordingly. Combined estrogen-gestagen therapy is administered either sequentially, with at least ten days of gestagen administration per month, or continually in combination. A seven-day hormone-free interval (as in oral contraceptive therapy) is no longer recommended, as it often leads to a worsening of symptoms.

Box 2

Types and modes of application of hormone therapy

ETestrogen therapy
EPTcombined estrogen-progestagen therapy
HThormone therapy (ET and EPT, orally and transdermally adminis-
tered systemic therapy)
Vaginal ETlow-dose vaginal estrogen therapy with little or no systemic effect
Open in a separate window

Various estrogens are used to treat climacteric symptoms. Estradiol, estradiol valerate, estriol, estriol succinate, and conjugated or esterized estrogens are available in various preparations ( Box 2 ). Systemic administration can be by the oral, transdermal, intranasal, or intramuscular route. For urogenital symptoms, estradiol is given as a vaginal tablet, ring, or cream; estriol is also given in these ways for this indication. Estradiol can be given transdermally (as a plaster or gel) in dosages from 0.25 to 0.1 mg/day. For the vaginal application of estradiol, there are vaginal tablets containing 0.025 mg/day, vaginal rings containing 0.075 mg/day, and creams containing 0.1 mg/day. The daily dose of estriol administered vaginally ranges from 0.02 to 0.5 mg/day. When estradiol is given orally, the bioavailability of the steroid is only 5%, because of a first-pass effect; on the other hand, when it is given transdermally, it is nearly 100% bio-available. This is why the usual doses vary depending on the route of administration. Drugs are very well absorbed when given vaginally. Conjugated estrogens contain a mixture of 10 different types of estrogen; their main components are estrone, equiline, 17β-dehydroequiline, and 17β-estradiol. After the oral administration of 2 mg of estradiol, serum levels of ca. 40–80 pg/mL are measured ( 10 ); similar levels are reached when 0.05 mg are given in the form of a plaster, or 3 mg in the form of a gel. It should be borne in mind that the vaginal administration of estrogens also gives rise to measurable serum concentrations. For example, when 0.5 mg of estriol is given vaginally, a serum estriol concentration of up to 100 pg/mL can be measured ( e5 ). Thus, vaginally administered estrogens can have systemic effects.

Estrogens for the treatment of climacteric symptoms

  • estradiol
  • estradiol valerate
  • estriol
  • estriol succinate

Tibolone, a norethinodrel derivative with estrogenic, androgenic, and gestagenic properties, is also used to treat climacteric symptoms ( 1 , 2 , e1 ). Before any hormone therapy is started, the indication should be carefully considered; the patient should be evaluated with extensive history-taking and physical examination, including a gynecological examination. Only in this way can the physician detect certain contraindications and health risks that might arise if HT were to be initiated ( Table ).

Table

The risks of perimenopausal hormone therapy*1
EndpointAbsolute risk
Thrombo-embolic eventsET: +6 events/10000 women/year (21 [HT] vs. 15 events [placebo])
EPT: +18 events/10000 women/year (35 [HT] vs. 17 events [placebo])
Any biliary diseaseET: +31 events/10000 women/year (78 [HT] vs. 47 events [placebo])
EPT: +20 events/10000 women/year (55 [HT] vs. 35 events [placebo])
Breast cancerET: −7 events/10000 women/year (26 [HT] vs. 33 events [placebo]) (ns)
EPT: +8 events/10000 women/year(38 [HT] vs. 30 events [placebo])
StrokeET (any stroke): +12 events/10000 women/year (44 [HT] vs. 32 events [placebo])
EPT (ischemic stroke): +8 events/10000 women/year (26 [HT] vs. 18 events [placebo])
Open in a separate window

*1Published data from the available studies in which absolute risk figures are given for the four endpoints in the left column of the table. These risks may be independent of the duration of therapy and the time of its initiation in relation to the age of menopause (see text; adapted from [2]).HT, hormone therapy; ET, estrogen therapy; EPT, estrogen-gestagen therapy: ns, not significant.

The effect of hormone therapy on climacteric symptoms

Many placebo-controlled, double-blind trials have shown that HT relieves vasomotor symptoms. It lowers the frequency of hot flashes by about 75%. Estrogens have been found to be effective, sometimes in combination with gestagens and tibolone. The reported side effects include breast tenderness, uterine bleeding, hemorrhage, arthralgia, emotional changes (irritability, loss of motivation, depression, other), and, less commonly, nausea, vomiting, headache, weight changes, rash, and pruritus (relative risk, 1.41; 95% confidence interval, 1,00–1.99) ( 7 ). The risks of other important clinical endpoints are mentioned in other subsections of this review. The efficacy of HT is rated as high in a position statement of the North American Menopause Society, published in 2010 and closely following the German S3 guideline in updated form. Estrogen therapy (ET) with or without the additional administration of gestagens is stated to be the most effective treatment for perimenopausal vasomotor symptoms. The latter are the main indication for HT ( 11 ).

The effect of hormone therapy on climacteric symptoms

Many placebo-controlled, double-blind trials of HT in symptomatic women have clearly revealed an effect on vasomotor symptoms.

The effect of hormone therapy on the quality of life

Only a very small number of randomized, placebo-controlled trials have addressed this issue, yielding inconsistent findings. It should be pointed out that the quality of life was not defined uniformly. No improvement in the quality of life was found in the WHI study, yet smaller-scale placebo-controlled trials that were conducted over relatively short times did, in fact, reveal that HT improved the quality of life. The consensus paper of the North American Menopause Society takes the position that it is unclear whether HT improves the health-related quality of life of asymptomatic women ( 11 ).

Urinary incontinence

A meta-analysis of 50 small-scale trials led to the conclusion that ET can partially or completely relieve urinary incontinence, particularly when an overactive bladder is the cause.

Vulvovaginal atrophy

Meta-analyses have led to the conclusion that HT by any route of administration improves the signs and symptoms of vaginal atrophy ( 12 , e6 ). Low-dose, local ET is just as effective as systemic ET. If symptomatic vaginal atrophy is the only indication for treatment, local vaginal ET should be given. This is the recommendation of both the German S3 guideline and the position paper of the North American Menopause Society ( 1 , 2 , 11 , e1 , e7 ).

Urinary incontinence

The various types of urinary incontinence have many different causes. Urinary incontinence can take one of two main forms: an overactive bladder, or stress incontinence. A meta-analysis of 50 small-scale trials led to the conclusion that ET can partly or completely relieve urinary incontinence, particularly when due to an overactive bladder ( 13 ). Two randomized trials, HERS and WHI, revealed that oral HT makes urinary incontinence worse ( 14 , 15 ). Transdermal or vaginal estrogen application improved incontinence to a not necessarily significant extent. Thus, oral HT should not be prescribed for the treatment of urinary incontinence; in cases of bladder overactivity, vaginal ET can be considered, in view of its favorable risk/benefit profile. The current state of the evidence is judged similarly in the position paper of the North American Menopause Society, in which it is stated that local ET can improve urge incontinence in patients with vaginal atrophy; on the other hand, its efficacy against stress incontinence is debated. It should be mentioned that various types of incontinence can be treated with non-hormonal medications, physical therapy, and operations whose efficacy is well documented ( 1 , 2 , 11 , e1 , e8 ).

Recurrent urinary tract infection

Estrogens have direct proliferative effects on the urethral and vesical epithelium. Further effects include a buildup of the vaginal epithelium and reconstitution of the vaginal flora, resulting in a lower frequency of colpitis. In small-scale trials, vaginal ET significantly reduced the frequency of urinary tract infections ( 16 ). On the other hand, oral HT has no protective effect of this kind. Vaginal estrogen is recommended for the treatment of recurrent urinary tract infections both by the North American Menopause Society and in the German S3 guideline ( 1 , 2 , 11 , e1 ). The relative risk is reduced by 36% to 75% ( 16 ).

Recurrent urinary tract infections

Vaginal estrogen treatment is recommended for recurrent urinary tract infections both by the German S3 guideline and by the North American Menopause Society.

Risk/benefit assessment

All the above makes clear that HT can be an effective method of treating climacteric symptoms. The decision whether or not to give oral or parenteral HT depends in large measure on the individual patient’s state of health. Perimenopausal women generally have fewer comorbidities than older, postmenopausal women. Meticulous history-taking is needed in any case before the treatment is initiated. Sex steroids can affect the risk of developing certain diseases. A thorough understanding of these risks is important, as they depend not only on the patient’s health profile, but also on the particular hormonal regimen used (ET, EPT) and on the duration of administration. Some risks are much greater than others. All patients should be adequately informed about the risks of their treatment.

Osteoporosis

HT has been found to lower the incidence of fractures both in observational studies and in randomized, controlled clinical trials ( 17 – 19 , e9 ). The clinical fracture rate is lowered, as is that of so-called osteoporosis-associated fractures. In general, however, the prevention and treatment of osteoporosis is not an issue for women seeking treatment for climacteric symptoms ( 1 , 2 , e1 ). Although EPT is an effective means of preventing osteoporosis, it cannot be recommended as a first-line therapy except in rare cases, in view of its unfavorable risk/benefit profile. The risks of ET, on the other hand, are commensurate with its benefits ( e10 ).

Cardiovascular diseases

Coronary heart disease

The WHI study revealed a mild elevation of the risk of cardiovascular events among women receiving HT. This was a surprising finding, as a protective effect had been expected in view of the biological effects of estrogens on lipoproteins and arterial vessels. The median age of the subjects in the WHI study was 60; one cannot, therefore, extrapolate the finding to healthy women around age 50 who are treated with estrogens (alone or in combination with gestagens) for climacteric symptoms. There is no evidence that such women have a significantly elevated risk of coronary heart disease. Indeed, there is evidence that, when ET is initiated early (after hysterectomy), it may actually lower the cardiovascular risk ( 20 , 21 ).

Risk/benefit assessment

The individual patient’s state of health is a very important consideration with respect to the indication for HT. Perimenopausal women generally have fewer comorbidities than elderly postmenopausal women.

Stroke

Randomized, controlled trials and meta-analyses of observational studies have revealed that ET and EPT elevate the risk of stroke. In the WHI, the relative risk was 1.39 for ET and 1.44 for EPT, while the absolute risk was +12 events per 10 000 women per year for ET, and +8 for EPT ( Table ). Tibolone roughly doubles the risk of stroke. Perimenopausal women have a low risk of stroke in any case but should be informed of the risk before ET or EPT is begun, in view of the seriousness of the condition.

Venous thromboembolism

The risk of venous thromboembolism is elevated in the first year of treatment to a greater extent than in later years; thus, special care should be exercised here. The absolute elevation of risk is + 6 events per 10 000 women per year under ET, and +17 under EPT ( Table ).

Biliary diseases

HT elevates the risk of biliary diseases. The risk is already elevated in the initial phase of treatment, particularly in overweight patients or those with a history of biliary disease ( 1 , 2 , e1 ).

Diseases of the central nervous system

Cognition

Meta-analyses have shown that neither ET nor EPT prevents the decline of cognitive functions in older, postmenopausal women. The putative cognitive effects of HT in younger postmenopausal and perimenopausal women are currently debated.

Dementia

Continuous combined HT elevates the risk of dementia in women over age 65. This fact, however, appears to be of little relevance for the decision whether to treat climacteric symptoms with HT ( 1 , 2 , e1 ).

Cardiovascular diseases

The WHI revealed that HT mildly elevates the risk of cardiovascular events.

Cancer

Breast cancer

EPT elevates the risk of breast cancer from the sixth year of treatment onward. Newer analyses of the WHI data have revealed that EPT administered early in the postmenopausal period can also elevate the risk of breast cancer within the first five years of treatment ( e11 ). In one study of ET, the risk of breast cancer was actually found to be lower after a mean duration of treatment of 5.9 years ( 21 ), but meta-analyses of randomized, controlled trials and observational studies have revealed an increased risk with more than 5 years of treatment ( e12 ). These meta-analyses also confirmed the risk-increasing effect of EPT and showed it to be markedly higher than that of ET. It can be concluded that ET must be given for a much longer time than EPT to elevate the risk of breast cancer. The significant lowering of the breast-cancer risk by ET in the WHI study is of unclear meaning ( 21 ). In summary, for women in the climacteric period who seek hormonal therapy of less than five years’ duration for their climacteric symptoms, an elevated risk of breast cancer is either not a consideration at all (ET), or not a major one (EPT).

Endometrial cancer

ET increases the risk of endometrial cancer in postmenopausal, non-hysterectomized women. This increase is large compared to the low-to-moderate increase in breast cancer risk. In women who have been under ET for more than three years, the relative risk of endometrial cancer is raised as much as fivefold; after ten years, as much as tenfold ( 19 , e13 , e14 ). When climacteric symptoms are treated with an appropriately constituted EPT, i.e., one in which gestagens are given at least ten days per month, the risk of endometrial cancer is not elevated.

Ovarian cancer

A meta-analysis of a large amount of study data revealed that HT raises the relative risk of ovarian cancer to 1.24. ET elevates the risk more than EPT does, and the risk is not elevated at all if the treatment is given for less than five years. HT for more than ten years has been found to raise the relative risk to 1.21 ( e15 ). On the other hand, an observational study that was conducted on a very large scale showed an increase of relative risk to 1.38 after a median follow-up of eight years. It is estimated that it takes one year of HT in 8300 women to produce one additional case of ovarian cancer ( 22 ).

Breast cancer

EPT raises the risk of breast cancer. An elevated risk has been demonstrated only after five or more years of EPT.

Colorectal cancer

Meta-analyses of observational studies have shown that the risk of colorectal cancer is about 20% lower in women who have undergone HT ( 23 ). In the WHI study, a significant lowering of the risk was found only in association with EPT; in most observational studies, however, both ET and EPT lowered the risk. Recent data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study have led to a renewal of debate on the subject: in this study, which was carried out on nearly 140 000 postmenopausal women, neither ET nor EPT had any significant effect on the risk of colorectal cancer ( 24 ).

HT after cancer

HT should not be given in the aftermath of any type of hormone-dependent malignant disease. As pointed out in the German S3 guideline, an analysis of the available evidence reveals, for example, that HT elevates the risk of recurrence in women who have been treated for breast cancer. The risk of recurrence of endometrial, ovarian, and colorectal cancer has not been adequately studied, and nothing can be said about other types of cancer in view of the lack of data. Thus, HT is contraindicated after breast cancer; after other types of cancer, particularly those that are hormone-dependent, decisions must be made on an individual basis. The main considerations here are factors such as hormone dependency, the risk of recurrence, and the scientific understanding of the oncogenic effect of HT ( 1 , 2 , e1 ).

Endometrial carcinoma

ET raises the risk of endometrial carcinoma in post-menopausal, non-hysterectomized women.

Overview

HT is the most effective means of treating climacteric symptoms. It can be recommended for the treatment of bothersome vasomotor symptoms and associated disturbances. Local ET is suitable for the treatment of vulvovaginal atrophy and recurrent urinary tract infections. Before HT is begun, the patient must be adequately informed of the risks and benefits, so that she can decide whether her climacteric symptoms are disturbing enough to warrant treatment with HT. Treatments other than HT are less effective or ineffective.

Ovarian carcinoma

A large-scale meta-analysis revealed that HT is associated with a relative risk of 1.24.

Further information on CME

This article has been certified by the North Rhine Academyfor Postgraduate and Continuing Medical Education. Deutsches Ärzteblatt provides certified continuing medical education (CME) in accordance with the requirements of the Medical Associations of the German federal states (Länder). CME points of the Medical Associations can be acquired only through the Internet, not by mail or fax, by the use of the German version of the CME questionnaire within 6 weeks of publication of the article. See the following website: cme.aerzteblatt.de

Participants in the CME program can manage their CME points with their 15-digit “uniform CME number” (einheitliche Fortbildungsnummer, EFN). The EFN must be entered in the appropriate field in the cme.aerzteblatt.de website under “meine Daten” (“my data”), or upon registration. The EFN appears on each participant’s CME certificate. The solutions to the following questions will be published in issue 25/2012.

The CME unit “Insect Stings: Clinical Features and Management”(Issue 13/2012) can be accessed until 11 May 2012. For issue 21/2012, we plan to offer the topic “Acute Confusional States in the Elderly”.

Solutions to the CME questions in issue 9/2012:

Horneber M et al.: Cancer-Related Fatigue.

Solutions: 1a, 2d, 3c, 4e, 5a, 6b, 7d, 8d, 9b, 10c

Please answer the following questions to participate in our certified Continuing Medical Education program. Only one answer is possible per question. Please select the answer that is most appropriate

Question 1

Which of the following climacteric symptoms are consistently present?

  1. Sleep disturbances and bodily symptoms
  2. Heat waves and vaginal dryness
  3. Urinary tract symptoms and sexual problems
  4. Mood changes and sleep disturbances
  5. Bodily symptoms and mood changes

Question 2

Oral hormone therapy elevates the risk of which of the following diseases?

  1. Urticaria
  2. Thromboembolism
  3. Acne vulgaris
  4. Osteoporosis
  5. Hip dysplasia

Question 3

By what percentage does hormone therapy reduce hot flashes?

  1. 15%
  2. 35%
  3. 55%
  4. 75%
  5. 95%

Question 4

What mode of application of hormone therapy is NOT effective for the treatment of vasomotor symptoms?

  1. transdermal
  2. oral
  3. vaginal
  4. nasal
  5. intramuscular

Question 5

A perimenopausal patient asks you for information about hormone therapy and the risk of venous thromboembolism. What should you tell her?

  1. Hormone therapy lowers the risk.
  2. Estrogen monotherapy changes the risk to the same extent as combined estrogen-progestagen therapy.
  3. The risk is markedly elevated in the first year of hormone therapy.
  4. Obesity and thrombophilia have no effect on the risk of venous thromboembolism.
  5. An elevated risk has only been observed after multiple years of hormone therapy.

Question 6

Hormone therapy elevates the risk of breast cancer. For what type and duration of therapy has this been demonstrated?

  1. ET for 3 years
  2. EPT for 3 years
  3. EPT for 5 years or more
  4. ET for 1 year
  5. EPT for 1 year

Question 7

What type of hormone therapy does NOT elevate the risk of endometrial carcinoma in women who have not undergone hysterectomy?

  1. pure ET
  2. EPT with five days of gestagen administration per month
  3. EPT with twelve days of gestagen administration per quarter
  4. EPT with five days of gestagen administration per quarter
  5. EPT with twelve days of gestagen administration per month

Question 8

What should you tell patients about hormone therapy and the risk of colorectal cancer?

  1. The risk of colorectal cancer can be reduced by hormone therapy.
  2. Even a short course of hormone therapy markedly lowers the risk.
  3. If colorectal cancer is diagnosed, hormone therapy must be stopped at once.
  4. Women with a family history of colorectal cancer can take prophylactic medication along with hormone therapy.
  5. Hormone therapy elevates the risk of colorectal cancer.

Question 9

How does estrogen therapy in the perimenopausal period affect the risk of stroke?

  1. +6 events/10 000 women/year
  2. +31 events/10 000 women/year
  3. 7 events/10 000 women/year
  4. 2 events/10 000 women/year
  5. +12 events/10 000 women/year

Question 10

A patient asks you about non-hormonal treatment of hot flashes. What should you tell her about the current state of scientific knowledge on this question?

  1. Isoflavones improve urogenital symptoms.
  2. Isoflavones are just as effective as hormone therapy for the treatment of hot flashes.
  3. Alternative methods are safer than hormone therapy.
  4. Serotonin reuptake inhibitors can improve the symptoms.
  5. Selective serotonin reuptake inhibitors have been approved for the treatment of climacteric symptoms.

Acknowledgments

Translated from the original German by Ethan Taub, M.D.

Footnotes

Conflict of interest statement

Prof. Ortmann is a paid consultant for Dr. Wolff Pharma and receives research support from medinova.

Dr. Lattrich states that no conflict of interest exists.

References

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2. Deutsche Gesellschaft für Gynäkologie und Geburtshilfe. S3-Leitlinie “Hormontherapie in der Peri- und Postmenopause” www.dggg.de/fileadmin/public_docs/Leitlinien/2-1-4-ht-lang-hp.pdf .
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Archives of Gynecology and Obstetrics
Arch Gynecol Obstet. 2012 May; 285(5): 1345–1352.
Published online 2011 Nov 29. doi:  [ 10.1007/s00404-011-2151-z ]
PMCID: PMC3325418
PMID: 22124532

The symptomatology of climacteric syndrome: whether associated with the physical factors or psychological disorder in perimenopausal/postmenopausal patients with anxiety–depression disorder

Borong Zhou ,corresponding author1 Xiaofang Sun ,2 Ming Zhang ,3 Yanhua Deng ,1 and Jiajia Hu 1

Borong Zhou

1Department of Neurology, The Third Affiliated Hospital of Guangzhou Medical College, Guangzhou, 510150 China

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Xiaofang Sun

2Research Institute of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical College, Guangzhou, 510150 China

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Ming Zhang

3Department of Epidemics and Health Statistics, Guangdong Pharmacy College, Guangzhou, 510240 China

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Yanhua Deng

1Department of Neurology, The Third Affiliated Hospital of Guangzhou Medical College, Guangzhou, 510150 China

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Jiajia Hu

1Department of Neurology, The Third Affiliated Hospital of Guangzhou Medical College, Guangzhou, 510150 China

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Author information Article notes Copyright and License information Disclaimer
1Department of Neurology, The Third Affiliated Hospital of Guangzhou Medical College, Guangzhou, 510150 China
2Research Institute of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical College, Guangzhou, 510150 China
3Department of Epidemics and Health Statistics, Guangdong Pharmacy College, Guangzhou, 510240 China
Borong Zhou, Phone: +86-20-81292101, Fax: +86-20-81292949, Email: [email protected] .
corresponding authorCorresponding author.
Received 2011 Aug 5; Accepted 2011 Nov 15.
Copyright © The Author(s) 2011
This article has been cited by other articles in PMC.

Abstract

Purpose

To explore whether the symptoms of climacteric syndrome associated with its physical factors or psychological disorder in perimenopausal/postmenopausal patients with anxiety–depression disorder.

Methods

We recruited 78 climacteric patients with anxiety–depression disorder and 72 control participants in perimenopausal/postmenopausal without anxiety–depression disorder for this study. We measured symptoms using the Greene Climacteric Symptom Scale in all cases. We also collected demographic data and tested sexual hormone, blood pressure, bone density, cognitive, estrogen receptor-alpha (ERα) gene polymorphism as physiological factors, using HARS-14 and CHDS assessed psychological disorder degree.

Results

C-MMSE scores as well as Estradiol and progesterone levels in the anxiety–depression disorder group were significantly lower compared to the control group (P < 0.01). In addition, the anxiety–depression disorder group had significantly higher Greene Climacteric Scale scores, as well as somatic symptoms compared to controls (P < 0.01). Moreover, the anxiety, depression and somatic symptoms of the Greene Climacteric Scale were positively correlated with HARS-14 and CHDS scores (P < 0.001) and negatively with estrogen level and C-MMSE scores (P < 0.05) in the anxiety–depression disorder group. Greene Climacteric Scale Symptoms were not significantly correlated with blood pressure, bone density or other factors (P > 0.05). There was no significant change in the allele frequency or the estrogen receptor-alpha gene polymorphisms, between the two groups (P > 0.05); however, the Pp genotype was negatively associated with C-MMSE scores (r = appraises, P = 0.033).

Limitations

The sample size was relatively small.

Conclusions

The symptoms of somatic symptoms in patients with climacteric syndrome and anxiety–depression disorder are associated with the emotional disorder but not with a physical disease. The Pp ERα polymorphism Pvu II is associated with a cognitive decrease.

Keywords: Climacteric, Anxiety–depression, Somatic symptoms, Cognitive, Physical disease

Introduction

Women in perimenopausal or postmenopausal, with the gradual degradation of ovarian function in the female hormone decreasing, can appear some physiological and psychological aspects of symptoms, main performance: hot, sweaty, tired, headache, dizziness, numb, sore limbs, attention poor, anxious and nervous, insomnia, mood swings, and sorrow depression, clinical called “menopause syndrome” or “climacteric syndrome” [ 1 , 2 ]. Depression or anxiety or depression combined anxiety (anxiety–depression) is a common psychological disorder in menopausal women. In SWAN 2010, 18% of elderly women had psychological disorders [ 3 ], and anxiety–depression in addition to have major depression, dropping interest, outside self-evaluation, anxiety, nervousness, tendency to get angry, and also may be associated with fatigue, insomnia, inattention, memory loss, pain and so on menopause syndrome-like symptoms. Two diseases have common some syndromes characteristic (especial somatic syndrome) easily confused in clinic, but also have difference risk for healthy. Although emotional disorders occur frequently in climacteric syndrome, climacteric syndrome that severely compromises life and work is rare. In contrast, anxiety–depression disorder has serious risk for women [ 4 ]. On the other hand, decline in the health of patients (e.g., hypertension and osteoporosis) often accompanies mild cognitive dysfunctions [ 5 , 18 , 20 ]. Some patients are excessively concerned about their health and visit clinics frequently, which can lead to many misdiagnoses and waste medical resources [ 6 , 7 ]. Do these patients have multisystem symptoms resulted from somatized anxiety–depression disorder or from truly organic diseases?

Reports on syndromes characteristic patients with anxiety–depression disorder in perimenopausal are limited. Are the multisystem symptoms of patients with anxiety–depression disorder in perimenopausal/postmenopausal as severe as their psychological ones? This question needs to be investigated further. Estrogen receptor (ER) polymorphisms are associated with many disorders including Alzheimer’s disease (AD), osteoporosis and coronary heart disease [ 8 – 11 ]; however, little is known about the association between ER polymorphisms and anxiety–depression comorbid with climacteric syndrome. In this study, we analyzed ER polymorphisms, sex hormone levels, psychological symptoms, cognitive function, blood pressure, bone density, menopausal transition (MT) stages and diseases course based on the Greene Climacteric Scale categories [ 12 ]. This study would be to recognise syndromes characteristic and provide the theoretical base for the early diagnosis of depression or anxiety in perimenopausal/postmenopausal.

Methods

Participants and sampling

Based on our study aim and requirements for statistical analyses, between 2007 and 2010, we recruited over 78 patients with anxiety and depression in perimenopausal and postmenopausal, as well as control participants with climacteric syndrome only. Concerning menopausal status we used the following definitions: perimenopausal women having irregular menses, less than 12 menses during the last 12 months and postmenopausal: no more menses in the last 12 months. All participants meet the Stages of Reproductive Aging Workshop (STRAW) criteria for peri/postmenopause, MT score of STRAW be −1 to +2 [ 2 ], combined with at least one symptom of climacteric syndrome. The age range of this sample was 40–60 years old. Exclusion criteria of All participants undergoing hormonal therapy, hormone therapy by implant in the preceding 6 months, endocrinopathies leading to menstrual irregularities, hepatopathies, thrombopathies, use of drugs which interfere in the menstrual cycle, anxiolytics and antidepressants (as their use indicates previous diagnosis of mood disorders), hysterectomy, oophorectomy, cancer or psychiatric disease or other severely organic diseases. This study was approved by the institutional review board of the Third Affiliated Hospital of Guangzhou Medical College (Guangzhou, China) and written informed consent was obtained from every participant.

We placed participants in the anxiety–depression group using the anxiety and depression diagnosis standard listed in ICD-10 [ 13 ]. The criteria include the following: (1) use of the Hamilton Anxiety Rating Scale-14 items (HARS-14) [ 14 , 15 ] and the Chinese version of the 17-item Hamilton Depression Rating Scale (CHDS) [ 16 ], all patients HARS-14 scores ≥14 and or CHDS ≥17; (2) experience of major anxiety symptoms for at least 3 months or major depression symptoms for at least 2 weeks; and (3) decline in functioning at work and home. Using these standards, we recruited 78 patients with major anxiety and or depression symptoms as anxiety–depression group, of whom 58 had mixed anxiety and depression disease(MADD, ICD-10 code F41.2), 13 of whom had anxiety only (ICD-10 code F41.8) and 7 of whom had depression only (ICD-10 code F32.0).The average age of these patients was 52.14 ± 5.74 years. Although somatization disorder is a somatoform disorder that overlaps with a number of functional somatic syndromes and has high comorbidity with major depression and anxiety disorders [ 17 ]. The study anxiety–depression patients were not coincided with somatization or somatization form disorder diagnosis criterion (ICD-10 code F45.0, F45.1).

Procedure

We recorded patient demographic information including age, education, disease course and menopausal status. Education level was defined as time spent in school. Disease course was defined as the duration of their symptoms in years; a disease course of over 6 months was considered to be 1 year. Menopause was defined as the cessation of menses for over 12 months according to SRTAW [ 2 ]. The early postmenopausal cases was 26 (33.33%) and 28 (38.89%) in anxiety–depression group and control group. There were no difference between them (P < 0.01). We used the HARS-14 and CHDS to determine anxiety and depression levels [ 14 – 16 ].

The Greene Climacteric Scale

We analyzed the characteristics of climacteric syndrome based on the Greene Climacteric Scale. In 2010, the validation and reliability of Greene Climacteric Scales (validation 0.68–0.76, reliability 0.83–0.87 in Chinese population) was reported by Zheng et al. in HongKang. The Greene Climateric Scale measures a total of 21 symptoms (Table  1 ) [ 12 , 18 ]. Each symptom is rated by the woman herself according to its current severity using a four-point rating scale: not-at-all symptoms (0); a little symptoms (1); quite a bit symptoms (2); extreme symptoms (3). The Greene Climacteric Scale scores include 21 items scores and an individual score within five symptom clusters: (1) anxiety symptoms (symptoms 1–6), (2) depression symptoms (symptoms 7–11), (3) somatic symptoms (symptoms 12–18), (4) vasomotor symptoms (symptoms 19–20) and (5) sexual function (symptoms 21). The mean score for each symptom is calculated by the sum of all individual scores divided by the number of subjects. The mean score of each symptom clusters are the mean scores of the symptoms within that cluster.

Table 1

Greene Climacteric Scale score comparisons between the anxiety–depression group and the control group (x ± s)

GroupsAnxiety–depression group (n = 78)Control group (n = 72)
1. Heart beating quickly or strong1.14 ± 0.78a0.56 ± 0.6
2. Feeling tense or nervous1.42 ± 0.86a0.63 ± 0.54
3. Difficulty in sleeping1.33 ± 0.81a0.58 ± 0.65
4. Excitable1.31 ± 0.86a0.37 ± 0.47
5. Attacks of panic0.74 ± 0.82a0.21 ± 0.35
6. Difficulty in concentrating1.11 ± 0.81a1.02 ± 0.62
7. Feeling tired or lacking in energy1.56 ± 0.83a0.38 ± 0.4
8. Loss of interest in most things1.05 ± 0.90a0.25 ± 0.32
9. Feeling unhappy or distressed1.20 ± 0.86b0.86 ± 0.51
10. Crying spells0.85 ± 0.90a0.18 ± 0.36
11. Irritability1.32 ± 0.93a0.47 ± 0.5
12. Feeing dizzy or faint1.42 ± 0.99a0.52 ± 0.38
13. Pressure or tightness in head or body1.23 ± 0.89a0.25 ± 0.31
14. Parts of body feel numb or tingling1.21 ± 0.85a0.52 ± 0.45
15. Headaches1.41 ± 0.91a0.98 ± 0.62
16. Muscle and joint pains1.27 ± 0.92a0.85 ± 0.49
17. Loss of feeling in hands or feet0.44 ± 0.70a0.24 ± 0.34
18. Breathing difficulties0.59 ± 0.76a0.18 ± 0.27
19. Hot flashes0.85 ± 0.88b1.29 ± 0.91
20. Sweating at night0.74 ± 0.77b1.06 ± 0.81
21. Loss of interest in sex0.85 ± 0.880.78 ± 0.61
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Using a Chi-square test a P < 0.01, b P < 0.05

The organic diseases diagnosis was based on the 2007 ESH-ESC (European Society of Hypertension-European Society of Cardiology) Practice Guidelines [ 19 ], the 2009 Osteoporosis Guidelines [ 20 , 21 ] and the standard for early detection of dementia, including mild cognitive impairment [ 22 ], blood pressure, poor recognition ability and low bone density. Our study used the Chinese Mini Mental State Examination (C-MMSE) [ 23 , 24 ] to assess the patient recognition function and the Fan Beam X-ray Bone Densitometer to assess bone density. We measured real-time blood pressure over 24 h to calculate patients’ average systolic and diastolic measurements.

Sexual hormone determination

We measured estradiol (E2), progesterone and testosterone levels using radioactive immunoassays. Peripheral vein blood was collected between 7:00 and 8:00 am. Blood from non-menopausal women were collected 3 days after their menstrual cycles. The variation of estradiol, progesterone and testosterone levels within anyone group was 5.6, 7.2 and 8.01%, respectively. The differences of estradiol, progesterone and testosterone levels between the groups were 6.5, 7.8 and 8.5%, respectively. The sensitivity of each ELISA assay was 0.01, 0.001 and 0.0001 pg/ml, respectively.

The analysis of polymorphisms in ERα genes, PvuII and XbaI primer design and synthesis

The sequence for the estrogen receptors is as follows: P1: 5′-CTGCCACCCTATCTGTATCTTTTCCTATTCTCC-3′; and P2: 5′-TCTTTCTCTGCCACCCTGGCGTCGATTATCTGA-3′. In descending order, the DNA molecular weight (Mark Shenzhen, Yishengtang Biological Enterprises Ltd.) of these receptors are 2,000 bp/1,600 bp/1,200 bp/800 bp/600 bp/400 bp/200 bp.

The method for genotyping estrogen receptors uses three steps. (1) Whole genomic DNA was extracted using the fast extraction method. (2) A polymerase chain reaction (PCR) where the total reaction estrogen receptor volume was 50 μL and comprised 34.3 μL sterile deionized water, 5 μL 10× PCR buffer, 200 µmol/L dNTP 4 μL, 40 pmol primers, 100 ng DNA template and 1 U TaqDNA polymerase. Reaction conditions consisted of a denature step at 94°C for 3 min, followed by 35 cycles of 94°C for 30 s, 61°C for 40 s, 72°C for 90 s, and a final extension at 72°C for 5 min. The extension product size was 1.3 kb. (3) Finally, a restricted enzymatic reaction was performed using 6 U PvuII and 10 U XbaI for enzymatic digestion, followed by a 1.2 agarose gel with ethidium bromide electrophoresis for 40 min, which was then photographed.

Two professional psychologists tested patients’ neurological and psychological statuses. Prior to these tests, both psychologists were trained to adjust and unify their standards.

Statistical analysis

All data were recorded as mean ± standard deviation (x ± s). We used SPSS 17.0 software for all statistical analyses. (1) ANOVA and ANCOVA rank-sum tests (i.e., variance arrhythmias) analyzed the demographic and symptomatic differences between the anxiety–depression group and the control group. (2) Pearson’s correlation analyzed the relationships between symptoms, psychological scores and physiological status. (3) Chi-square tests analyzed the frequency of estrogen receptor-alpha polymorphisms. (4) Multifactorial logistic analyses analyzed the relationship between the ERα polymorphism and other symptoms such as sex hormone levels, psychological scores (HARS-14 and CHDS) and cognitive functions. A P value of less than 0.05 was considered significantly different.

Results

Differences in demographic information, HARS-14, CHDS, C-MMSE, Greene Climacteric Scale scores and sexual hormone levels between groups

As shown in Table  1 , there were significant differences between the anxiety–depression group and the control group (P < 0.001) in all areas except difficulty in concentrating and sexual interest. The vasomotor symptoms scores as well as the facial redness and evening sweating scores for the anxiety–depression group were significantly lower (P < 0.05) compared to the control group; all other anxiety–depression group scores were higher than the control group (P < 0.01). As shown in Table  2 , the Greene climacteric Scale scores of anxiety, depression and somatic symptoms were significantly higher in the anxiety–depression group (P < 0.001) compared to control group, although the vasomotor symptoms scores were significantly lower (P < 0.05). The HARS-14 and CHDS scores of the anxiety–depression group were significantly higher than the control group (P < 0.001) whereas the E2 and progesterone levels were significantly lower (P < 0.001). The cut-off score for the statistics in Table  2 is 27 (mild cognitive difficulty [ 21 ]. An ANCOVA rank sum test (variance arrhythmias) showed that the C-MMSE score in the anxiety–depression group was significantly lower than the control group (P < 0.01). There were no significant differences in age, testosterone level, bone density, systolic and diastolic blood pressure between the two groups.

Table 2

Comparison of Greene Climacteric Scale, HARS-14, CHDS, and C-MMSE scores, as well as sexual hormone levels, bone density and average blood pressure (x ± s)

GroupsAnxiety–depression group (n = 78)Control group (n = 72)P value
Age (years)52.14 ± 5.7451.55 ± 4.870.576
Education (years)8.95 ± 2.63b10.57 ± 3.670.010
Disease time of anxiety and depression (years)4.18 ± 3.410/
HARS-14 score16.42 ± 9.32a5.54 ± 2.730.000
CHDS score15.4 ± 8.02a4.6 ± 1.860.000
C-MMSE score26.97 ± 1.88a28.92 ± 0.720.000
E2 (pg/ml)133.63 ± 161.32a304.83 ± 248.640.000
Testosterone (pg/ml)0.89 ± 0.331.12 ± 0.210.143
Progesterone (pg/ml)4.68 ± 10.08a15.34 ± 27.000.000
Whole body bone density1.022 ± 0.1191.024 ± 0.1090.738
BlAv Mean systolic pressure (mmHg)140.94 ± 21.59138.48 ± 15.290.681
Average diastolic pressure (mmHg)80.78 ± 13.6578.96 ± 10.810.127
Anxiety symptoms1.19 ± 0.52a0.56 ± 0.350.000
Depression symptoms1.21 ± 0.61a0.41 ± 0.370.000
Somatic symptoms1.09 ± 0.54a0.57 ± 0.590.000
Vasomotor symptoms0.83 ± 0.70b1.12 ± 0.840.025
Sexual function symptoms0.85 ± 0.890.78 ± 0.610.452
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Using a Chi-square test, aP < 0.01, bP < 0.05

Correlation analysis between Greene Climacteric Scale symptoms with general condition, psychological score, bone density, average blood pressure in anxiety–depression disorder group

As shown in Table  3 , Pearson’s correlational analyses, revealed positive correlations between Greene Climacteric Scale anxiety, depression and somatic symptoms scores with HARS-14 and CHDS scores (P < 0.001) as well as negative correlations between E2 and progesterone levels and C-MMSE scores (P < 0.05) within the anxiety–depression group. There was also a positive correlation between education years in the anxiety–depression group. There was an additional correlation between vasomotor symptoms and HARS-14 scores, whereas sexual factors were correlated with CHDS scores (P < 0.05). There was no significant correlation between Greene Climacteric Scale scores and blood pressure, bone density, menopause, disease course or other factors (P > 0.05).

Table 3

Correlation analysis between the Greene Climacteric Scale symptoms with general condition, psychological score, bone density and average blood pressure in anxiety–depression disorder group

Variations
Correlation factorsCo-efficientP value
Anxiety symptoms
 Education years0.2350.039
 E2−0.3710.001
 Progesterone−0.3100.007
 HARS-140.7950.0001
 CHDS0.7910.0001
 C-MMSE−0.3430.002
Depression symptoms
 E2−0.2490.028
 HARS-140.5600.0001
 CHDS0.6130.0001
 C-MMSE−0.2420.033
Somatic symptoms
 E2−0.3250.004
 HARS-140.6390.0001
 CHDS0.7110.0001
 C-MMSE−0.3800.001
Vasomotor symptoms
 HARS-140.2270.046
Sexual factors
 CHDS0.2620.020
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Polymorphism analyses on the ERα gene

We used P, pX or x to indicate restriction enzymes. Lowercase letters indicated the digestion sites of the enzyme, whereas capital letters indicated the absence of restricted enzyme sites. The PvuII restriction enzyme distinguishes between three genotypes: PP (1.3 kb), Pp (1.3 kb + 850 bp + 450 bp) and pp (850 bp + 450 bp). The XbaI restriction enzyme distinguishes between three genotypes: XX (1.3 kb), Xx (1.3 kb + 910 bp + 390 bp), and xx (910 bp + 390 bp; Fig.  1 ).

An external file that holds a picture, illustration, etc.
Object name is 404_2011_2151_Fig1_HTML.jpg

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Fig. 1

Left the endonuclease PvuII distinguished three genotypes: PP (1.3 kb), pp (850 bp + 450 bp) and Pp (1.3 kb + 850 bp + 450 bp). Right the Endonuclease Xba I gene distinguished three genotypes: Xx (1.3 kb + 910 bp + 390 bp), xx (910 bp + 390 bp) and XX (1.3 kb)

ER gene polymorphisms and the allele frequency distribution

Table  4 shows the allele frequency of the ERα Pvu II and Xba polymorphisms. The allele frequencies of the studied sample were consistent with the Hardy–Weinberg Genetic equations and representative populations. The genotype distribution in the anxiety–depression group was PP17.95%, Pp39.74%, pp42.31%, XX10.26%, Xx32.50% and xx57.69%. The allele frequency for P and X is 37.81 and 26.28%, respectively. Both groups have a majority of p and x gene sites. As shown in Table  4 , there were no significant differences between the anxiety–depression and control groups in the genotypes of the ERα PvuII or Xba I polymorphisms.

Table 4

The analysis of ERα Pvu II genotypes and allele frequencies

GroupsPvuII restriction enzyme genotype (%)Allele (%)XbaI restriction enzyme genotype (%)Allele (%)
PPPpppPpXXXxxxXx
Anxiety–depression group (n = 78)14 (17.95)31 (39.74)33 (42.31)37.8162.198 (10.26)25 (32.50)45 (57.69)26.2873.72
Control group (n = 72)15 (20.83)34 (47.22)23 (31.90)44.4455.5611 (15.27)26 (36.11)35 (48.61)33.3366.67
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Using a Chi-square analysis, we found no significant differences between the two groups in the six genes (χ2 = 0.66–1.65, P > 0.05)

The correlation between ER gene polymorphisms and anxiety–depression symptoms

One-way factorial analyses indicated that the Pp and pp genotypes were correlated with anxiety, depression, and organic diseases, as well as CHDS, HARS-14 and C-MMSE scores. The xx genotype was correlated only with organic disease and vasomotor symptoms. When we introduced the ten factors above into a multifactorial logistic model, only the Pp genotype and C-MMSE scores were negatively correlated (y = 4.51 × 1.043 − 2.22, r = −0.108, 95% CI 0.014 ~ 0.883, P = 0.033).

Discussion

Our study shows that HARS-14, CHDS and Greene Climacteric Scale scores of anxiety, depression and somatic symptoms were significantly higher in perimenopausal/postmenopausal patients with anxiety–depression disorder compared to a control group, whereas E2 and Progesterone levels were significantly lower (P < 0.01). These findings indicate that, in addition to anxiety and depression disorders, somatic symptoms are characteristics of climacteric patients with anxiety–depression disorders. This finding is also consistent with a previous report using Greene Climacteric Scale results [ 25 , 26 ]. Using a Pearson’s correlation analysis, we found that a decreased E2 level is correlated with anxiety, depression and somatic symptoms, which in turn might be correlated with the onset of anxiety–depression disorder. Previous work by other researcher corroborates this finding [ 27 , 28 ]. Additionally, our study indicates that anxiety, depression and somatic symptoms are correlated with psychological scores but not with blood pressure, bone density, menopause or disease course. These findings indicate the following: (1) the Greene Climacteric Scale is valid for determining climacteric patients with anxiety and depression disorders; and (2) the somatic symptoms in climacteric patients with anxiety–depression disorders might be correlated with emotional disorders only [ 28 , 29 ] and not with organic diseases, such as hypertension and osteoporosis.

The anxiety–depression group showed a significant decrease in vasomotor symptoms, which is positively correlated with the HARS-14 score. This result is inconsistent with our other findings. Based on the symptoms of patients with anxiety–depression disorder, our study shows that there is correlation between vasomotor symptoms and the occurrence of anxiety disorders. Patients with light anxiety may keep their symptoms hidden, whereas patients with severe anxiety may show vasomotor. However, patients with anxiety–depression disorder showed a significant decrease in vasomotor symptoms, indicating that these symptoms may be characteristic of climacteric syndrome. Seritan and others have shown that vasomotor symptoms in patients with climacteric syndrome are closely associated with psychological status [ 28 , 30 ]. Although we sampled patients with climacteric syndrome and anxiety–depression disorder, our results are consistent with previous findings. A recent report has shown that the somatic symptoms in climacteric syndrome might be the accumulative effect of anxiety and facial redness, which is also consistent with our observations [ 29 ].

Our study found a correlation between education level and anxiety and depression symptoms, indicating that people with more education are more likely to be anxious during menopause. This finding is inconsistent with the study by Kakkar et al. [ 1 ]. We did not find a significant change in sexual interest in the anxiety–depression group compared to the control group; this finding is also not consistent with the SWAN report. Asian attitudes toward sex-related issues tend to be conservative, which could explain our results. There seems to be no change in the sexual interest of patients with anxiety and depression. Moreover, our study indicated that sexual behavior is negatively correlated with depression scores, which is consistent with previous findings [ 3 , 31 ].

The transcription factor of ER is located in the cytosol and nucleus and includes two isoforms: ERα and ERβ. Human ERα is located on the 6q24–27 gene [ 8 ] and includes eight exons and seven introns, at a total length of 140 kb. In the first ERα gene intron, we found a T to C mutation at 0.4 kb upstream of the second exon, and an A to G mutation 50 bp downstream of the locus, resulting in the restriction sites for PvuII and XbaI, respectively, thus creating a restriction site polymorphism [ 8 , 9 ]. Previous studies have shown that the ERα gene polymorphism is correlated with hot flashes and vaginal dryness but not with emotional disorders in patients with climacteric syndrome [ 32 ].

Our study indicates that the allele distribution of anxiety–depression genotypes is PP17.95%, Pp39.74%, pp42.31%, XX10.26%, Xx32.50% and xx57.69%. The allele distribution frequency for the P and X alleles is 37.81 and 26.28%, respectively. The majority of alleles are p and x. Statistical analysis revealed no significant differences in the genotypes of the ERα PvuII and XbaI genes. Moreover, there was no correlation between the ERα allele and anxiety or depression symptoms. This finding is consistent with Malacara [ 32 ]. Based on a multifactorial logistic analysis, there is a negative relationship between the Pp genotype in the ERα gene and the C-MMSE score in the anxiety–depression group (r = −0.108, P = 0.033).

Brandi et al. [ 8 ] showed that the PPXX genotype of ERα were more frequent in patients with Alzheimer’s disease (AD), compared to a control group [ 8 ]. Estrogen level decrease is correlated to AD. Estrogen protects neurons. Estrogen therapy has positive effects on anxiety–depression disorder, cognitive malfunction and AD in patients with climacteric syndrome [ 33 ]. Depression related to aging may be a symptom of early-onset AD [ 8 ]. The SWAN report found that 18% of older women have emotional disorders and that depression was significantly correlated with impaired cognitive function [ 5 ]; however, there was no such correlation between emotional symptoms and cognitive malfunction in patients with climacteric syndrome [ 34 ]. In our study, we showed that anxiety, depression and somatic symptoms were negatively correlated with C-MMSE scores in the anxiety–depression group; however, there was no such correlation in the control group. Thus, these findings are consistent with SWAN report which suggest cognitive decline correlation with anxiety and or depression, but not climacteric syndrome. There is a negative correlation between the Pp genotype in the ERα gene and C-MMSE scores, which is inconsistent with Olsen’s report. In Olsen’s study, the XbaI genotype XX was negatively correlated with impaired cognitive function in postmenopausal [ 35 ]. Recently, Kim et al. [ 36 ] reported similar results. The inconsistent results may be relation to the difference of samples. Is there a correlation between impaired cognitive function of emotion disorder and the occurrence of mild cognitive impairment (e.g., MCI or early-onset AD)? Are the ERα polymorphism and decreased estrogen levels common or different mechanisms in patients with climacteric syndrome as well as anxiety–depression disorders and patients with AD? These questions need to be further investigated in perimenopausal/postmenopausal patients with anxiety–depression disorders.

Conclusion

The somatic symptoms in patients with climacteric syndrome are correlated with emotional disorders but not with organic diseases. There was no correlation between the ERα allele polymorphism and anxiety or depression symptoms, whereas the Pp genotype of the ERα Pvu II gene may be related to impaired cognitive function in patients with anxiety or depression symptoms.

Acknowledgments

This work was supported by the Natural Science Foundation of Guangdong Province, in China (06022385).

Conflict of interest

The authors declare that they have no conflict of interest.

Open Access

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

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