6.1 Overview

Women diagnosed with breast cancer may experience menopausal symptoms secondary to:

          (i)   diagnosis of breast cancer occuring concurrently with natural menopause

          (ii)  withdrawal of hormone replacement therapy following breast cancer diagnosis

          (iii) menopause induced by breast cancer treatment (GnRH agonist therapy, oophorectomy or 
                 chemotherapy), and

          (iv)  side effects of adjuvant endocrine therapy including tamoxifen and aromatast inhibitors

6.1.1 Natural Menopause

It is important to remember that reproductive aging occurs concurrently with somatic aging and symptoms experienced by women may relate to the normal aging process rather than menopause.  Longitudinal studies demonstrate that only vasomotor symptoms (including hot flushes and night sweats), symptoms of genitourinary atrophy and sleep disturbance have a consistent association with oestrogen deficiency (Management of Menopause-Related Symptoms (2005). However, a variety of other symptoms may be experienced by peri- and postmenopausal women as reported by participants in the longitudinal Melbourne Women’s Midlife Health Project (see Figure: Symptoms reported by Australian women). Hot flushes, night sweats, vaginal dryness, and insomnia increase in severity across the menopause transition whereas breast tenderness decreases. Multiple factors influence menopausal symptomatology (see Table: Factors influencing menopausal symptoms).

Figure: Symptoms reported by Australian women

Table: Factors influencing menopausal symptoms.

Data derived from Dennerstein et al., (2000)

6.1.2 Menopause symptoms related to breast cancer treatments

Medically induced menopause (chemotherapy or surgery) and ovarian suppression with GnRH agonists are associated with vasomotor and urogenital symptoms which can be more frequent and severe than those experienced by women without breast cancer (Couzi, Helzlsouer et al. 1995; Carpenter, Andrykowski et al. 1998; Crandall, Petersen et al. 2004; Knobf 2006). Mood and cognitive problems as well as a reduction in quality of life are observed in women treated with BC chemotherapy who then experience menopause (Andersen, Anderson et al. 1989; Knobf 1998; Rostom 2001; Ganz, Greendale et al. 2003). Sexual dysfunction, joint pain, headaches and fatigue are also reported (Knobf 2006). However, it is often difficult to separate out the effects of BC/BC therapy versus menopausal experience (Duffy, Greenberg et al. 1999). The prevalence of sleep disturbance in menopausal women ranges from 20-70% (Bower 2008). Multiple factors have been identified as contributing to sleep problems with vasomotor symptoms reported as an important contributor to insomnia in women with BC (Bower 2008). Younger women with BC who experience chemotherapy-induced premature menopause report more physical symptoms, psychological distress and poorer sexual functioning compared with other BC survivors (Young-McCaughan 1996; Ganz, Rowland et al. 1998). Persistent physical complaints including vasomotor symptoms are associated with an increased risk of moderate to severe psychological distress, including anxiety and depression. (Cohen, Soares et al. 2006) (Schag CA, Ganz PA et al. 1993). The incidence of menopausal symptoms related to adjuvant endocrine therapy is shown in Table: Frequency of menopausal symptoms with adjuvant endocrine therapies. Up to 20% of breast cancer patients cease/consider ceasing endocrine therapy due to menopausal symptoms (Barron, Connolly et al. 2007) (Fallowfield, Cella et al. 2004).

Table: Frequency of menopausal symptoms with adjuvant endocrine therapies.

Data derived from (Fallowfield, Cella et al. 2004; Del Mastro, T et al. 2005; Bernhard, Zahrieh et al. 2007; Eisen, Trudeau et al. 2008)

6.2 Vasomotor symptoms: Hot flushes and night sweats

A hot flush may be defined as a subjective sensation of heat localized to the upper part of the body (chest, arms and head) with a mean duration of 3-4 minutes and associated with objective signs of cutaneous vasodilatation and a subsequent drop in core body temperature. Hot flushes are frequently accompanied by sweating, palpitations, irritability and anxiety. The pathophysiology of hot flushes remains unclear; however, altered serotonin and noradrenalin levels secondary to oestrogen withdrawal are postulated to result in changes in the hypothalamic thermoregulatory set point resulting in the hot flush sensation (Freedman 2005). The reported prevalence of hot flushes in natural menopause varies (related to population differences or study limitations); affecting up to 85% of peri- and 66% of postmenopausal women, with severe symptoms observed in 10-20% of women. Hot flushes usually commence during the menopausal transition with the highest frequency reported around the final menstrual period then declining during the postmenopausal phase (Politi, Schleinitz et al. 2008). The mean duration of vasomotor symptoms in the Melbourne Women’s Midlife Health Project cohort was 5.2 years with 23% of women reporting flushing at year 13 of follow-up (Col, Guthrie et al. 2009).

Vasomotor symptoms, reported in up to 80% of women with breast cancer (particularly younger women), may be more severe and frequent compared to women without breast cancer although direct comparisons are lacking (Couzi, Helzlsouer et al. 1995; Carpenter, Andrykowski et al. 1998; Crandall, Petersen et al. 2004; Knobf 2006). The natural history of vasomotor symptoms in women with breast cancer, including average duration, is unknown at present. However, a decrease in the frequency of hot flushes at 6.3 years post diagnosis was reported in a longitudinal study of BC survivors (Ganz, Desmond et al. 2002). GnRH agonist therapy was associated with more hot flushes at 3 months and fewer hot flushes at 36 months compared with chemotherapy where the peak number of hot flushes occurred 6 months after treatment commenced (Bernhard, Zahrieh et al. 2007).

See Management of vasomotor symptoms.

6.3 Urogenital symptoms

6.3.1 Natural menopause

Urogenital symptoms are common, affecting up to 50% of postmenopausal women and tending to increase with age since menopause (Suckling, Kennedy et al. 2010). Some women may be reluctant to volunteer these symptoms. Vaginal changes secondary to oestrogen deficiency include thinning, shortening and narrowing of the vagina with decreased elasticity, blood flow, and secretions. Increase in vaginal pH from acid to more alkaline alters vaginal microbial flora with predisposition to urinary tract infections.  Vaginal atrophy results in symptoms of vaginal dryness or discomfort, burning, pruritis and dyspareunia (Trinkaus, Chin et al. 2008). In contrast to vasomotor symptoms, atrophic vaginitis is more prevalent during the postmenopausal period and is usually progressive. Smokers and women who are sexually inactive have an increased risk of vaginal atrophy. Postmenopausal atrophy of urethral and bladder mucosa may result in urinary urgency/frequency, increased risk of cystitis and incontinence.

6.3.2 Women with breast cancer

Urogenital symptoms are frequently problematic in women with breast cancer with 50-75% of BC survivors reporting one or more symptoms (Trinkhaus, Chin et al. 2008); especially those women taking aromatase inhibitors (see Table: Frequency of menopausal symptoms with adjuvant endocrine therapies). Increased vaginal dryness and urinary incontinence was reported by BC survivors at 6.3 years of follow-up in a longitudinal study (Ganz, Desmond et al. 2002).

See Management of Urogenital symptoms.

6.4 Sexual dysfunction

6.4.1Sexual dysfunction and menopause

Sexual dysfunction occurs when the woman “perceives that she has an inability to experience sex as she would wish” (thus causing distress) and encompasses problems with desire/libido, arousal, orgasm and sexual pain (including dyspareunia and vaginismus). Sexual dysfunction is common in the Australian general community with 50% of women reporting lack of interest and 20-27% reporting pain or lack of pleasure with sex. In addition, data from the Melbourne Women’s Midlife Health project indicate a significant decline in sexual functioning across the natural menopause transition; the percentage of women reporting sexual dysfunction increasing from 42 to 88% (Dennerstein, Alexander et al. 2003). The decline in sexual functioning across the natural menopause transition correlates with falling oestradiol (but not testosterone) levels; however, the relationship between hormone levels and sexual dysfunction remains unclear.  Women may be reluctant to disclose concerns regarding sexual dysfunction and sensitive direct questioning may be necessary. Sexual dysfunction is multi-factorial and results from the interplay of both physiological factors (for example, age, illness, menopausal status, effect of medication)  and psycho-social functioning (for example, cultural influences, education, self-image, partner/relationship issues, concurrent depression and anxiety) (see Table: Risk factors associated with sexual dysfunction). Sexual dysfunction is increased in women with early/premature menopause or surgical menopause. In women with natural menopause, the four factors correlating best with sexual function are a woman’s psychological health, her relationship with her sexual partner, her expectations regarding the relationship’s future and her past sexual experience.
 

Table: Risk factors associated with sexual dysfunction

6.4.2 Sexual dysfunction in women with breast cancer and menopause

Sexual dysfunction is common in women with BC; reported in 70% of Australian BC women in a recent prospective study (Panjari, Bell et al. 2011). A decline in sexual activity with time since BC diagnosis was observed in a longitudinal study (Ganz, Desmond et al. 2002). In addition, younger women with chemotherapy-induced premature menopause report more physical symptom distress and poorer sexual functioning than other BC survivors (Young-McCaughan 1996; Ganz, Rowland et al. 1998; Knobf 2006). Dyspareunia related to vaginal atrophy leading to decreased sexual desire is the commonest symptom of sexual dysfunction reported in young women with breast cancer (Schover 2008). Multiple physical and psycho-social factors are associated with increased sexual problems in women with BC and include: particular BC treatments (chemotherapy, oophorectomy, GnRH agonists and endocrine adjuvant therapy), vaginal dryness, poorer mental health,  partner's difficulty understanding one's feelings, more severe body image problems, fatigue and ethnicity (Fobair, Stewart et al. 2006; Schover 2008; Trinkaus,Chin et al. 2008). Older woman or those unpartnered report less sexual dysfunction (see Table: Risk factors associated with sexual dysfunction and Table: Frequency of menopausal symptoms with adjuvant endocrine therapies).

See Management of sexual dysfunction.

6.4.3 Female Androgen Insufficiency

Androgen deficiency/insufficiency may be due to disorders affecting the hypothalamus/pituitary, adrenals, ovaries or factors causing an increase in sex hormone binding globulin and therefore affecting bioavailable testosterone. The causes of androgen deficiency  in women are varied (see Table: Causes of Androgen deficiency in women). The female androgen insufficiency syndrome (Bachmann et al., Princeton Consensus statement 2001) comprises the key symptoms of reduced libido, diminished well being and lowered mood in the setting of a low bioavailable testosterone and adequate oestrogen levels. Hypoactive sexual desire disorder is defined by DSM IV in both men and women as persistently recurrent deficient (or absent) sexual fantasies and desire for sexual activity which causes marked distress or interpersonal difficulties and is not due to another mental disorder, medical condition or drug. However, there is a lack of sensitive and reliable testosterone assays (Managing Menopause - Measurement of Testosterone in Women) and normative data with poor correlation between symptoms and androgen levels both in women with and without BC (Davison, Bell et al. 2005; Dennerstein, Lehert et al. 2005; Schover 2008). Short term clinical trials of testosterone (often using supraphysiogical doses) have demonstrated improvement in aspects of sexual function, cognitive function and bone mineral density in postmenopausal women without cancer (Davis, Moreau et al. 2008). However, an 8 week randomized placebo controlled trial of transdermal testosterone in BC women with low libido demonstrated no benefit (Barton, Wender et al. 2007). Use of testosterone in clinical practice is limited by poor assays, lack of normative data, uncertainty about clinical efficacy and lack of safety data.  The Endocrine Society guidelines (Santen, Allred et al. 2010) recommend against making the diagnosis of androgen deficiency in women due to “inadequate indication and lack of long term safety data” with a call for additional research.
 

Table: Causes of Androgen deficiency in women

SHBG- Sex hormone binding globulin
 

6.5 Depression/ Mood disorders

6.5.1 Natural menopause

Anxiety and depression are the leading causes of burden of disease in Australian women (Australian Institute of Health and Welfare, 2003). The menopause transition may be a time of psychological vulnerability for some women; however, the evidence is conflicting as to whether natural perimenopause/menopause is associated with an increased risk of de novo depression. Studies are limited by poor and varied measurement methods and design. However, depressive symptoms are common at menopause (see Figure: Symptoms reported by Australian women). Observational data suggest that anxiety symptoms increase during the menopausal transition independently of depression and vasomotor symptoms.

6.5.2 Women with Breast Cancer

The diagnosis of cancer elicits greater distress compared with other medical diagnoses (Shapiro, Lopez et al. 2001). The diagnosis of breast cancer may lead to psychological dysfunction (Payne, Hoffman et al. 1999; Mantani, Saeki et al. 2007) with associated adverse effects on quality of life (Andersen, Anderson et al. 1989; Knobf 1998; Rostom 2001; Ganz, Greendale et al. 2003). However, the relative contributions of menopause and the BC diagnosis/ treatment to psychological distress are often difficult to determine (Duffy, Greenberg et al. 1999). 

The prevalence of depression and/or anxiety in women with BC is approximately twice that of women in the general population. Depression and/or anxiety was observed in almost 50% of BC women (Kissane, Grabsch et al. 2004; Burgess, Cornelius et al. 2005) in the year following diagnosis which then persisted in 25% of women at 4 years and 10% of women at 5 years (Burgess, Cornelius et al. 2005). Disease status, treatment and psychosocial factors contribute to the risk of depression/anxiety and include chemotherapy, oophorectomy, positive oestrogen receptor status, previous psychological treatment, persistent physical symptoms, lack of an intimate confiding relationship, younger age, and severely stressful non-cancer life experiences (Schag CA, Ganz PA et al. 1993Andritsch, Goldzweig et al. 2004; Burgess, Cornelius et al. 2005; Badger, Segrin et al. 2007; Sayakhot, Deeks et al. 2011). The degree/pattern of psychological distress also varies with age (Knobf 2006) and time since diagnosis (Burgess, Cornelius et al. 2005; Ganz, Kwan et al. 2011). An increased risk of psychological distress, including depression and anxiety, is observed with surgical menopause and premature/early menopause in women with and without breast cancer (Duffy, Greenberg et al. 1999; Rostom 2001; Taylor 2001; Ganz, Greendale et al. 2003; Duffy, Allen et al. 2005; Knobf 2006).

Body image problems are also common in women diagnosed with BC, occurring in up to 50% (Avis, Crawford et al. 2004; Fobair, Stewart et al. 2006). Increased body image problems were associated with mastectomy, hair loss from chemotherapy, concern with weight gain or loss, poorer mental health, lower self-esteem, and partner's difficulty understanding one's feelings. Women with premature menopause as a result of surgery or chemotherapy have lower self-confidence and self-concept (Schover 1994; Pasquali 2002) and also more negative body image (Bellerose and Binik 1993; Schover 1994; Avis, Crawford S et al. 2004)

6.5.3 Psychological distress in women with premature menopause link to early menopause website

See the Early Menopause website - Management of mood disorders for more information.
 

Selected References

Bachmann GA, Bancroft J et al., Female androgen insufficiency: The Princeton consensus statement on definition, classification and assessment Fertil Steril (2001) 77: 665-670

Dennerstein L, Dudley EC  et al., A prospective population-based study of menopausal symptoms Obstet Gynecol (2000) 96: 351-358.

Dennerstein L, Lehert P et al., Sexuality.  American Journal of Medicine (2005) 118 Suppl 12B:59-63.

Hickey M, Saunders C et al., Practical guidelines for assessing and managing menopausal symptoms after breast cancer. Ann Oncol (2008) 19:1669-1680.

Panjari, M., R. J. Bell, et al. (2011). "Sexual function after breast cancer." J Sex Med 8(1): 294-302.

Soules MR , Sherman S et al., Executive summary: Stages of reproductive aging workshop (STRAW). Fertil Steril. (2001) 76:874-878.

7. Diagnosis

Content updated May 16, 2011