Managing the menopause and hormone therapy
The primary reason for instituting treatment of a menopausal woman is to alleviate symptoms that impair the quality of life and to optimise health and wellbeing, both short and long term. The latter includes addressing issues such as prevention of bone loss, cardiovascular disease and diabetes risk.
Menopause – definition: the last menstrual period. This occurs at an average age of 51.5 years, but earlier in smokers and following hysterectomy.
The menopausal transition begins with variation in menstrual cycle length and ends after 12 months of amenorrhea.
The stages of the menpause have been classified according to a woman’s reported bleeding pattern supported by changes in pituitary follicle stimulating hormone levels (FSH). The ‘perimenopause’, which means ‘about the menopause’ describes the time from which menses become irregular and FSH levels have increased through until 12 months after the last menstrual bleed. The term ‘postmenopause’ is applied to women who have not experienced a menstrual bleed for at least 12 months. Defining menopause in a woman who has had a hysterectomy prior to the natural cessation of ovarian function requires measurement of the pituitary gonadotropin FSH which should be elevated with a concurrently low estradiol level. The real clinical challenge is the determination of the menopausal status of a woman using systemic steroid contraception which not only suppresses menses but also suppresses FSH production and endogenous estradiol. In most instances however such classification is academic rather than clinically required.
Surgical menopause refers to menopause induced by removal of both ovaries prior to natural menopause. Menopause is considered to be premature when it occurs in a woman before the age of 40 years. Spontaneous premature ovarian failure affects 1% of women by age 40 and 0.1% by age 30.
Physiology of the menopause
The young ovary consists of incompletely developed ova or germ cells surrounded by specialized hormone producing cells which form a supportive structure. The follicular cells which produce estrogen encase the developing ova in multiple little nests or follicles. Before birth the ovaries of a healthy 20 week old fetus contain approximately 7.5 million immature ova. By birth this number has fallen to two million and by puberty only about 300,000 remain. Menopause occurs when there is extensive deterioration of the follicular cells and the immature ova within. Thus the necessary sex hormones can no longer be produced and fertilizable ova can no longer develop. Blood levels of the hormones estrogen and progesterone fall and women at this time may experience symptoms of estrogen insufficiency.
It is not understood why so many ova are necessary in the first place, or what determines their loss. When the number of healthy ova reaches 25 000, at approximately 37 years of age, the rate of loss accelerates, culminating in menopause at the average age of 51.5 years. When the rate at which the ova disappear is accelerated earlier either spontaneously or by environmental factors such as cigarette smoking, menopause occurs earlier.
Oestradiol, progesterone and testosterone are the main steroid hormones produced by the ovaries under the direction of the pituitary gland. The pituitary produces FSH which act on the ovaries to stimulate the development of a mature egg every 28 days, and LH (luteinizing hormone) which stimulates ovulation. This pituitary function in turn is controlled by the hypothalamus which acts as the master control box for reproductive function.
When the integrity of the ovarian follicular cells deteriorates, oestradiol levels fall and this change is detected by both the hypothalamus and the pituitary gland. In addition, the production by the ovaries of a protein called ‘inhibin’ diminishes. The pituitary gland responds by producing greater amounts of both FSH in an attempt to drive ovarian function. Therefore as menopause approaches, blood levels of inhibin decline and FSH and LH levels rise. Serum oestradiol levels remain relatively unchanged or may increase approaching the menopause, but are usually well preserved until the late perimenopause. This is presumed to be in response to elevated FSH levels. However, the menopause transition is characterized by marked, and often dramatic, variations in FSH and oestradiol levels such that measurements of these hormones are unreliable guides to menopausal status.
Oestrogen biosynthesis is catalyzed by aromatase cytochrome P450. Following menopause, oestradiol is primarily produced in extragonadal sites and acts locally at these sites as a paracrine or even intracrine hormone. These sites include the mesenchymal cells of adipose tissue, osteoblasts and chondrocytes of bone, the vascular endothelium and aortic smooth muscle cells, and numerous sites in the brain. Within these sites, aromatase action can generate high levels of oestradiol locally without significantly affecting circulating levels. Circulating levels of estrogens in postmenopausal women thus reflect “spill over” of oestradiol into the circulation from the peripheral tissues in which oestradiol is being produced and where it acts .
In contrast to the fall in oestradiol during menopause, total and free testosterone (T) levels, as well as dehydroepiandrosterone sulfate (DHEAS) and androstenedione decline with age and an effect of natural menopause on circulating androgen levels is not seen. Thus specific tissue effects of natural menopause cannot be attributed to loss of androgenic hormone production. However, women who have had their ovaries surgically removed or who have had their ovaries damaged by chemotherapy or radiotherapy or who have ovarian gonadotropin suppression will have loss of ovarian androgen production as a result.
The fall in oestradiol at menopause has effects on non-reproductive tissues. There are two oestrogen receptors (ER), ERaand ERb expressed in varying amounts in the brain, vascular tissues, bone, cartilage, the urogenital tract and so forth. The ligand-binding domains of both ERs are capacious and promiscuous and are thus able to accept a variety of ligands which may act as agonists, antagonists or elicit mixed agonist/antagonist responses. This has been attributed to the unique three dimensional conformation induced by the binding of the ligand to the ER which in turn determines how the ligand bound receptor will behave. This complex molecular biology explains why plant chemicals (phytoestrogens), environmental chemicals (xenoestrogens) and the new class of therapeutic compounds known as oestrogen agonist/antagonists (EAAs) can activate the ERs. Futhermore we know that growth factors and other such compounds can activate the ER in the N-terminal region of the receptor (known as the AF1 region) and elicit oestrogen–like actions without acting as traditional ligands, and therefore not actually being estrogens in the classical sense.
Menstrual irregularity is considered to be the earliest indication of the menopause transition (perimenopause). Because of the hormone fluctuations leading up to and around the time of menopause, women may experience intermittent symptoms ranging from hot flushes and night sweats when oestradiol levels fall through to breast tenderness and swelling and heavy or irregular bleeding when oestradiol levels rise in response to FHS drive. Commonly reported symptoms are listed below. Women may experience none of these symptoms, or several. Symptoms of menopausal hormonal changes may start several years before menopause, even whilst regular periods are occurring due to the changing hormone levels. Symptoms may last for few to many years in some women. There is no cut-off age at which menopausal symptoms begin or end.
Change in sleep quality is a hallmark of menopause. Although more common amongst women with vasomotor symptoms, disturbed sleep architecture may occur independently of vasomotor symptoms. The three forms of sleep disorders associated with menopause include insomnia/depression, sleep disordered breathing, and fibromyalgia. The mechanism underlying this change in sleep pattern is not known; however, treatment of insomnia may be an important indication for hormone therapy.
There is increasing evidence that depression is a perimenopausal symptom experienced by some women. Women with a history of depression and/or PMS are more likely to report depressed mood during the menopausal transition. The vulnerability to depression is heightened in the perimenopause and declines during the late menopause transition.
Arthralgia is a common menopausal symptom that occurs with increasing frequency as women progress though the menopausal stages, with the occurrence being associated with FSH levels . The strongest evidence that arthralgia is a consequence of estrogen depletion is the high incidence of arthralgia in women treated with aromatase enzyme inhibitors after breast cancer.
At least 50 percent of postmenopausal women suffer symptoms of urogenital atrophy, including vaginal dryness, dyspareunia, recurrent urinary tract infections and urge and stress incontinence. Incontinence is not a life threatening condition, but it can severely impair quality of life and in many instances result in incapacitation. A systematic meta-analysis reported a beneficial effect of oestrogen on incontinence, particularly urge incontinence. In contrast data from two RCTs indicate that exogenous estrogen therapy may worsen urinary incontinence. However, consistently studies show benefits of vaginal oestrogen for dyspareunia and urinary symptoms.
The most commonly reported menopausal symptoms include:
- hot flushes and night sweats
- sleep disturbance
- anxiety and irritability, emotional lability
- joint aches and pains
- vaginal atrophy
- fatigue and diminished well-being.
Physical consequences include:
- bone loss due to increased bone re-absorption
- central abdominal weight gain
- conversion to a more adverse cardiovascular risk lipid profile
- stress and urge incontinence
Although bone loss is not a presenting symptom as such, many postmenopausal women will present to their doctor to discuss the findings of a routine bone density study. There evidence from systematic reviews or large, high-quality randomised controlled studies that oestrogen insufficiency results in bone loss and increased osteoporotic fracture risk in postmenopausal women, which can be prevented with oestrogen therapy. Oestrogen therapy has been shown to reduce bone turn over, increase bone mineral density (BMD) and decrease vertebral fracture rates by up to 40 percent. Available data indicate the menopause-related BMD decrement is very evident during the first year since menopause (lumbar spine: -8.1%/year; forearm: -3.4%/year), and progressively decreases, according to a logarithmic function usually settling at a rate of -1-2 % per annum, with considerable inter-individual variation.
With the loss in oestrogen at menopause there is a significant increase in central abdominal fat accumulation irrespective of no change in total body weight.
The odds of developing the metabolic syndrome increases after the last menstrual period even after adjusting other risk factors.
The menopause is accompanied by a transition from a gynoid to an android pattern of body fat distribution and an increase in total body fat without a significant change in total percent body fat. Increases are seen in both truncal and subcutaneous abdominal fat mass, with the greatest change seen in intra-abdominal fat mass. This has been reported to increase by as much as 20% to 44%. The accumulation of central abdominal fat in women at this time is associated with a decline in circulating adiponectin. Adiponectin, an adipokine produced by fat, increases insulin sensitivity by promoting fat oxidation distally in liver and muscle. Low serum adiponectin levels are associated with insulin resistance (IR) and the metabolic syndrome such that the decline in adiponectin with intra-abdominal weight gain at menopause is believed to have an important role in the development of IR after menopause.
Total cholesterol, LDL-cholesterol and apo-B levels increase across the menopausal transition, resulting in an increased cardiovascular disease risk profile.
Diagnosis of menopause
For naturally menopausal women not using exogenous hormones, the primary criteria for defining the stages of the menopause transition are based on menstrual bleeding. The Stages of Reproductive Aging Workshop suggested that the menopausal transition could be characterized by specific stages (the STRAW classification). The transition years are described in two stages by STRAW, with early transition being variable cycle length and increased FSH and late transition being greater than 60 days of amenorrhea and increased FSH. The postmenopausal period is described as early, up to 5 years from the final menstrual period, and late, beyond 5 years. Research supports an interval of amenorrhea of 60 days or more as highly predictive of the onset of the late menopausal transition. Hence for women with an intact uterus the menopause transition is diagnosed clinically by change in the bleeding pattern and eventually amenorrhea.
This approach is not useful for women who cannot report their menstrual pattern because of prior hysterectomy or endometrial ablation or use of a progestogen intra-uterine device or for women who are using systemic hormonal contraception. Hormone measurement may be useful in the former, but such measures are uninformative for the latter group of women. For young women with amenorrhea, premature ovarian failure is a diagnosis that requires the measurement of oestradiol and gonadotropins.
The laboratory testing that confirms menopause is an elevated FSH in the setting of a low oestradiol level. However in the early menopause transition serum FSH and oestradiol may be very erratic. Specific cut off levels vary considerably between laboratories according to the assays used. Biochemical testing is only required for women who cannot describe their underlying cycle or perhaps for younger women with amenorrhea for whom the differential diagnosis may include hyperprolactinemia, exercise or weight loss induced amenorrhea and so forth.
The diagnosis of premature ovarian failure requires at least 4 months of amenorrhea and 2-3 serum FSH values greater than 40 mIU/mL, obtained at least 1 month apart, in women less than 40 years of age. The only way to determine if a woman using systemic steroid contraception in her late forties or early fifties is menopausal is to have her cease the treatment and evaluate her after 6 to 8 weeks for recurrence of natural menses and symptoms. If menses have not recurred, consider measurement of FSH and oestradiol.
Why do women seek HRT today?
Because of all the bad press regarding HRT most women consider it a last resort. Many women do not present because of hot flushes, but rather because of depression or sleep deprivation. They may also present because of low libido secondary to vaginal atrophy. It is not uncommon for women to try a number of over-the-counter options and see and alternative therapy practitioner before discussing their menopausal symptoms with their doctor.
Commonly used alternatives to HRT
A systematic review of the published quality trials of complementary and alternative medical approaches to the management of menopausal symptoms reported insufficient data to support the consistent effectiveness of such approaches. However, individual trials and clinical guidelines do indicate that some women experiencing mild menopausal symptoms may gain relief by dietary modification and lifestyle changes, such as reduction in smoking, caffeine and alcohol, stress management and increased exercise. A recent Cochrane Review concluded that evidence to support a benefit of exercise for the treatment of vasomotor symptoms is lacking. Acupuncture has not been shown to have a meaningful effect on vasomotor symptoms in quality trials. Strong evidence to support benefits from either relaxation or training in breathing techniques are lacking.
Many women are seeking bio- identical hormones. This is now a multi-million-dollar industry based on sophisticated packaging of pseudoscience to consumers. It is costly, safety data is lacking in terms of doses and no uniform patient information is provided to consumers. As a consequence women being treated with these therapies (sex hormones dispensed as lozenges or troches or compound that creams) are unaware of risks. With the increasing popularity of porcine or bovine thyroid gland extracts many women are being treated for a diagnosis of hypothyroidism which they don't actually have. Similarly an increasing number of women are being diagnosed and treated for "adrenal fatigue" based on 24 hour urinary cortisol collections. There is no scientific basis for such a diagnosis and treatment with glucocorticosteroids in this setting is inappropriate.
Women often pursue these treatments for some time and then become concerned that they are expensive and that they are uncertain of the safety. This may well precipitate a consultation with their usual general practitioner regarding menopause.
Recommendations regarding the use of hormone therapy
Hormone replacement therapy (HRT) is the most effective intervention for the treatment of menopausal symptoms.
Women who have undergone hysterectomy should be treated with oestrogen alone whereas women who still have a uterus need to receive oestrogen plus progestin.
Treatment for the symptomatic perimenopausal woman who finds her symptoms distressing, is directed at controlling irregular cycling and/or heavy bleeding, ensuring contraception if required and providing relief from other symptoms at the lowest effective dose. Improvement in quality of life is what most of these women are seeking and advice on dietary and lifestyle modifications as well as pharmacological and non-pharmacological treatment is important.
For the perimenopausal woman needing contraception, the combined oral contraceptive pill provides contraception, regular predictable and lighter withdrawal bleeds, and relief from vasomotor and other symptoms. It also preserves bone density, helps prevent ovarian and endometrial cancer and treats acne that can occur at this time. Each woman’s risks must be assessed to determine the suitability of this approach even though the dose of hormones is low. This should include smoking status, blood pressure, lipid profile, migraine aura history, DVT and cardiovascular risk and family history.
In the menopause transition the ovaries have variable activity due to fluctuating FSH levels resulting in random hypo- and then hyper-estrogenic states. During the late menopause transition phase the endometrium is stimulated by the increase in estrogen production. The levonorgestrel releasing intrauterine device (LNG-IUD) provides contraception at this time if required, as well as suppressing the endometrium. Although initially spotting is not uncommon after insertion, about 80% of women will become amenorrheic at one year. The direct delivery of low dose progestogen to the uterus provides contraception, treatment of menorrhagia and endometrial protection when combined with continuous oral or transdermal estrogen and the LNG-IUD can be left in situ for 5 years. The low dose minimizes the side effects.
Oral progestogen only regimens (medroxyprogesterone acetate and micronized progesterone) have been shown to provide relief from hot flushes when given in high doses as well as preventing endometrial hyperplasia. However side effects of the progestogen such as weight gain, mastalgia, fluid retention, vaginal discharge, and dry mouth can be a problem at these doses. Short-term use may be applicable in women who do not want to take estrogen. It can be used cyclically for the first 12-14 days of the cycle and produce predictable bleeding in the majority of women.
For women who are less than 12 months postmenopausal, who have not had a hysterectomy:
- oestrogen should be administered continuously with progestin given for at least 14 days per month to induce a withdrawal bleed-such therapy provides no contraception.
- oestrogen can be given continuously with a progestin impregnated IUD (Mirena ®) inserted to provide continuous endometrial protection;
- a low dose oral contraceptive pill can be continued if there are no safety concerns (risk assessment for thrombosis and cardiovascular risk needs to be undertaken).
Women unable to use, or who choose not to use hormonal therapy in the perimenopause may get some relief from other treatments for example selective serotonin or noradrenaline reuptake inhibitors, gabapentin, or clonidine although effects are less than for oestrogen.
The primary use of HRT is to alleviate symptoms of the menopause, namely hot flushes, night sweats, sleep disturbance, arthralgia and vaginal dryness and therefore improve the quality of life of women who without HRT find these symptoms intolerable. For women with an intact uterus progestogen therapy is taken with oestrogen to protect the lining of the uterus from over stimulation by oestrogen. This can be cyclic for 14 days out of a monthly cycle, or as continuous-combined HT when both the oestrogen and progestogen are taken every day. Cyclic HT results in scheduled menstrual bleeding; whereas no bleeding occurs with continuous-combined HT in 90% of women after twelve months. If breakthrough bleeding is persistent or prolonged then investigation of the endometrium is required.
For women at least 12 months postmenopausal, both estrogen and progesterone can be given continuously.
Oral oestrogen preparations include conjugated equine oestrogens, synthetically derived piperazine oestrone sulphate, oestriol, micronized oestradiol and oestradiol valerate.
Oestradiol may also be given transdermally as a patch or gel, as a slow release percutaneous implant and most recently as a transdermal skin spray. Non-oral estrogen administration results in a more physiological balance between oestradiol and oestrone. It can be very useful for women with elevated triglyceride levels or significant liver function abnormalities. Non-oral therapy is also less likely to affect sex hormone binding globulin and thyroid binding globulin levels. Oestradiol pellets (implants) containing pure crystalline 17-oestradiol have been available for over 50 years. They are inserted subcutaneously into the anterior abdominal wall or buttock.
Common adverse effects of oestrogen include nausea, headache, breast tenderness, and when given with a progestogen, erratic or sometimes heavy bleeding. Cyclic oestrogen-progestogen therapy is recommended for women who have not experienced 12 months of amenorrhea. Initiating therapy with the lowest dose of oestrogen often will minimize breast tenderness, unscheduled bleeding and potentially other adverse effects. Transdermal or transvaginal estrogen is less likely than oral oestrogen to cause nausea and headache. Also, transdermal oestrogen is associated with a lower incidence of breast tenderness and deep vein thrombosis than oral oestrogen. Changing from one oestrogen regimen to another in many cases can alleviate certain adverse effects.
The addition of a progestogen to oestrogen for a postmenopausal woman with an intact uterus is required to protect against endometrial hyperplasia and endometrial carcinoma. Duration of progestogen use remains under debate however this becomes a moot point if women abandon HRT use due to progestogen side effects or unwillingness to resume menstrual bleeding. Indeed epidemiological data indicates alarmingly high rates of endometrial hyperplasia and cancer amongst women supposedly on adequate cyclical regimens indicating that either in reality compliance is poor or that endometrial protection is inadequate, or both.
Oral administration of progesterone is convenient; however, the oral micronized form is rapidly metabolized and inactivated in the liver. Therefore high doses must be administered to achieve adequate circulating blood levels. Synthetic progestogen is more resistant to hepatic metabolism. Hence lower doses can be used to achieve the desired endometrial effect. Yet, there is up to a 10-fold variation in the bioavailability of the various progestogens following oral administration. Side effects are reported by a small, but significant number of women with both progesterone and synthetic progestin therapy. Natural micronized progesterone taken orally may induce sedation and undesirable hypnotic effects and synthetic progestogens may cause adverse mood effects in some women. Intramuscular progesterone administration results in predictable circulating levels but the injection is painful and inconvenient. The vaginal route results in therapeutic levels in the endometrium. Vaginal gels and tablets of micronized progesterone are commonly used in in vitro fertilisation protocols. Transvaginal progesterone used in an alternate day regimen for 12 days has been shown to be effective as part of a cyclic HT regimen. But, long term this route of administration is inconvenient and unsatisfactory for most women. A vaginal levonorgestrel impregnated intrauterine device is available in some countries and in appropriate circumstances is an excellent option for progestogen effects to be achieved in the endometrium with minimization of systemic side effects.
The absolute contraindications to oestrogen +/- progestogen therapy include undiagnosed vaginal bleeding and current treatment of a hormone dependent malignancy. Past oestrogen-dependent malignancy is a strong relative indication against hormone therapy, and some would consider this to be an absolute contraindication to treatment. Other important relative contraindications against the initiation of HT include past VTE disease (oral oestrogen in a fully anticoagulated individual may be acceptable as may be transdermal oestrogen), frequent migraine with aura (which in itself is a risk factor for stroke), active endometriosis, severe liver disease, unstable major systemic disease, being over the age of 65 years or a strong family history of breast cancer.
- For women aged 50 to 59 years users of HRT have a lower all cause mortality than non-users.
- HRT protects against bone loss and both vertebral and non vertebral fractures.
- Treatment should be commenced with low dose oestrogen as many women will find this sufficient to manage their symptoms.
Very low doses of vaginal oestrogen relieve symptoms and normalize vaginal atrophy. Intravaginal oestrogens include topical oestradiol in the form of a ring or pessary, oestriol in pessary or cream form.
Oestrogen used vaginally or systemically reduces the symptoms of overactive bladder.
Vaginal oestrogen reduces the incidence of recurrent urinary tract infections.
Use of oestrogen alone and oestrogen plus a progestinin has been associated with a decrease in the risk for type 2 diabetes.
Initiation of HRT is associated with lesser accumulation of weight, fat mass, and/or centrally located fat mass.
E alone-commencement immediately after menopause is not associated with an increase in breast cancer risk / commencement > 5 years postmenopausal associated with a significant reduction in risk (RR0.58: CI 0.36-0.93).
E+P is associated with increased risk of breast cancer which increases with duration of use.
Tibolone is a synthetic compound that exhibits oestrogenic, progestogenic and androgenic actions. It is effective in the management of vasomotor symptoms and reduce its urogenital atrophy. It has been shown to improve sexual function. Unlike oral estrogen progestin therapy it does not increase mammographic density. Its use is associated with an increase in bone mineral density and a reduction in vertebral and hip fractures. In older women it has been associated with a small increased risk of ischaemic stroke to a similar extent to that seen for oral oestrogen.
Duration of HRT
All women should be reviewed at least annually. Some women may require long term therapy for symptom control
Early menopause / premature ovarian failure
Based on expert opinion, women who have undergone an early menopause are usually advised to use estrogen therapy, with progestin if they have a uterus, until they reach the age of natural menopause.
Bio-identical hormone therapy
There is no evidence either for or against the safety and efficacy of hormonal products described as bio- identical or compounded estrogen and progesterone therapy. The primary concern is that women using compounded oestrogen with progesterone receive adequate progesterone to protect their endometrium as several cases of endometrial cancer have now been reported in users of compounded sex steroids.
There is limited evidence to support the efficacy of complementary therapies for the management of menopausal symptoms. Many women find these therapies effective, however this is often due to a placebo effect as has been shown in the number of randomised controlled trials of complementary therapies.
These compounds, found in a wide variety of edible plants, may display both oestrogenic and anti-oestrogenic effects. Systematic reviews of intervention studies questions the validity of the proposed benefits of phytoestrogen supplementation, with little data in postmenopausal women to support a role for phytoestrogens as an alternative for conventional HRT.
Black cohosh (Cimicifuga racemosa, also known as Actaea racemosa) is a North American native plant. It has common usage internationally for the treatment of hot flushes and sweats experienced by postmenopausal women. Overall, results of randomized controlled trials do not suggest black cohosh is useful in the treatment of hot flushes.
Women who flush appear to have greater sympathetic nervous system activity and the drug clonidine, a centrally acting a-adrenergic antihypertensive, may act by elevating the “flush threshold”. Clonidine 50 to 150 mcg twice daily has been used for many years to alleviate hot flushes with limited effectiveness. Some women experience side effects at very low doses (dry mouth).
Gabapentin was developed for the treatment of epilepsy. It is also used for neurogenic pain, restless-leg syndrome, essential tremor, bipolar disorder and migraine prevention. However doses of 300-900mg at night have been shown to be efficacious in reducing the frequency and severity of hot flushes. More somatic complaints were reported with gabapentin than with oestrogen or placebo however it is still represents a nonhormonal alternative to oestrogen for some women.
Serotonin reuptake inhibitors (SSRIs)
SSRIs have been studied as alternatives to estrogen to reduce hot flushes and improve mood disorders in women unable to use hormone therapy. Studies of venlafaxine a serotonergic-noradrenergic reuptake inhibitor, and paroxetine, an SSRI, indicate a moderate reduction in vasomotor symptoms with doses of 37.5 to 75mg and 12.5 to 25 mg per day respectively. Both therapies may cause nausea and insomnia. In addition, venlafaxine may cause dry mouth, constipation and decreased appetite whereas paroxetine may cause headaches.