Summary More than 40 RCTs have found that oestrogen improves vasomotor symptoms. Systematic reviews of RCTs have found that oestrogen improves urogenital symptoms and depressed mood. Important adverse effects include venous thromboembolic disease, breast cancer, and endometrial cancer.

Benefits
Vasomotor symptoms: We found no systematic review. We found over 40 RCTs comparing oestrogen versus placebo and various preparations and/or routes against each other. Most found that oestrogen reduced vasomotor symptoms (data from one RCT in 875 women: odds ratio 0.53, 95% confidence interval 0.31 to 0.93).³ Two RCTs found that transdermal oestrogen at a low dose of 25 µg daily reduced severity of vasomotor symptoms compared with placebo. ^{4 5} Urogenital system: We found one systematic review (search date 1995) and three subsequent RCTs. The review pooled data from six RCTs.⁶ It found that oestrogen improved urogenital symptoms regardless of the route of administration (no figures available). One subsequent RCT (n=136) found that low dose transdermal oestrogen (25 µg daily) combined with norethisterone acetate significantly reduced vaginal dryness and dyspareunia compared with placebo over six months.⁴ Two other RCTs (n=192) found that local administration of oestrogen using a silicone oestradiol releasing vaginal ring over 24-36 weeks improved vaginal oestrogenisation and pH compared with placebo. ^{7 8} One of these trials also found a significant reduction in incidence of urinary tract infection in treated women (P=0.008).⁷ Psychological symptoms: We found one systematic review (search date 1995, 14 RCTs, 12 cohort studies), which found that oestrogen reduced depressed mood among menopausal women.⁹ Duration of treatment ranged from one month to two years. Data pooling for oestrogen versus placebo (10 studies) found that oestrogen reduced depressive symptoms (no figures available). We found no RCTs of oestrogen treatment in women with clinically proved depression. We found one systematic review (search date 1996, 10 controlled trials, 9 observational studies) of the effects of oestrogen on cognitive function in postmenopausal women and women with Alzheimer's disease.¹⁰ Studies were too weak to allow reliable conclusions. An additional crossover RCT (n=62) found a beneficial effect of oestrogen on sleep quality compared with placebo over seven months.¹¹ Quality of life: We found no systematic review. We found four RCTs (639 women, 3 RCTs placebo controlled, 3 versus progestogen), which found significant improvement in quality of life in women treated with oestrogen compared with baseline or placebo.^12-15 The largest RCT (242 women) found that oestrogen improved quality of life (P=0.0003) and wellbeing (P=0.003) compared with placebo over 12 weeks.¹²

Harms
Many RCTs have found that oestrogen causes weight gain and breast tenderness in the short term. Although many women report an increase in weight when starting oestrogen, we found no evidence from RCTs that oestrogen causes significant weight gain in the long term. The most important long term adverse effects are increased risk of venous thromboembolic disease, endometrial cancer, and breast cancer.^16-18 The relation between oestrogen (as hormone replacement therapy) and breast cancer was reviewed in a reanalysis of 51 studies of more than 160 000 women.¹⁹ The review found that the risk of breast cancer increased by 2.3% (1.1% to 3.6%) each year in women using hormone replacement therapy. Five or more years after hormone replacement therapy was stopped, there was no significant excess of breast cancer.¹⁹

Comment
Many studies used selected populations such as women attending hospital clinics, who may be different in their behaviour, personality, and symptom profile to women of the same age seen in primary care or those who do not seek medical advice.

Benefits
We found no systematic review. Vasomotor symptoms: We found five RCTs (257 women, all trials less than a year long), which found that women taking progestogens experienced a significant reduction in vasomotor symptoms compared with placebo.^20-24 The single RCT comparing oestrogen alone with progestogen (150 mg of depot medroxyprogesterone for 25 days a month) found that over three months, 18% of women taking oestrogens and 33% taking progestogen reported no vasomotor symptoms.²¹ One RCT (n=102) found that transdermal progesterone cream 20 mg daily improved vasomotor symptoms compared with placebo (P<0.001) but had no beneficial effect on bone density.²⁵ Urogenital system: We found no RCTs evaluating the effects of progestogens alone on urinary incontinence, the lower genital tract, or sex life. Psychological symptoms: We found no RCTs. Quality of life: One RCT of cyclical progestogen plus oestrogen for six months found no evidence of an effect on quality of life.²⁶ We found no studies of progestogen alone on quality of life.

Harms
We found two RCTs that evaluated harms of progestogens. The first compared continuous progestogen (norgestrel) and placebo in 321 women who had undergone hysterectomy and were already taking conjugated oestrogen. It found no difference in symptoms (including weight gain and bloating).²⁷ The second RCT (875 women) compared various oestrogen-progestogen combinations over three years.³ It found that additional progestogen increased breast discomfort (odds ratio 1.92, 1.16 to 3.09). Neither trial found evidence of an effect on cardiovascular events.

Comment
Progestogen is seldom given alone, which makes it hard to isolate its effects. When it was given without oestrogen, doses of progestogens were high, the lowest dose being 20 mg medroxyprogesterone acetate per day.

Benefits
We found no systematic review. Vasomotor symptoms: We found three RCTs, two of tibolone versus continuous combined oestrogen/progestogen treatment over 48 and 52 weeks (672 women with menopausal symptoms) ^{28 29} and one versus placebo over 16 weeks (82 women with menopausal symptoms).³⁰ The first RCT found a slightly greater reduction in hot flushes with the combined regimen than with tibolone over 48 weeks (P=0.01). The second trial found a significant reduction in vasomotor symptoms from baseline in both groups (67/72 women on HRT and 58/68 women on tibolone, P<0.001) but no significant difference between groups. The third trial found tibolone reduced vasomotor symptoms by 39% compared with placebo (P=0.001). Urogenital system: We found two RCTs. The first RCT found no significant difference between tibolone and combined hormonal treatment in terms of subjective reports of vaginal lubrication; both interventions improved lubrication compared with baseline.²⁸ The second RCT (437 women) found that tibolone improved sexual satisfaction compared with oestradiol plus norethisterone (P<0.05).³¹ We found no RCTs examining effects on urinary incontinence. Psychological symptoms: We found no RCTs. Quality of life: We found no RCTs. Bone density: We found nine RCTs, which found that tibolone increased bone density over periods from 6 to 36 months compared with baseline or placebo.³²

Harms
We found no evidence on adverse effects from RCTs. One non-randomised controlled trial found that the main unwanted effect of tibolone was breakthrough bleeding, which occurred in about 10% of users.³³ We found no good evidence of androgenic adverse effects such as hair growth and greasiness of the skin. Two RCTs of short term use found a 33% reduction in plasma high density lipoproteins with tibolone, ^{34 35} although the long term effects on cardiovascular disease are unknown.

Comment
None.

Benefits
We found no systematic review. Vasomotor symptoms: We found three placebo controlled RCTs. Two evaluated soy supplements, which contain phyto-oestrogen, using double blind designs; the other, which was not blinded, evaluated isoflavone. The first RCT (58 postmenopausal women) compared soy flour versus wheat flour for 12 weeks and found that hot flushes were reduced significantly more in the group of women using soy flour (40% v 25% reduction).³⁶ The second RCT used a crossover design to evaluate six weeks' administration of 34 mg soy protein daily. It found reduced severity but not frequency of vasomotor symptoms.³⁷ The third RCT (n=51) used a crossover design to compare isoflavone 40 mg daily with placebo. It found benefit from placebo compared with baseline, but not with isoflavone.³⁸ Urogenital system: We found no RCTs. Psychological symptoms: We found no RCTs. Beneficial effects of treatment on quality of life: We found no RCTs.

Harms
We found no evidence of significant adverse effects.

Comment
None.

Benefits
We found no systematic review. Vasomotor symptoms: We found two RCTs. ^{39 40} One crossover RCT (66 women) found that clonidine reduced the mean number of flushing attacks in the 14 days after crossover compared with placebo (56.8 v 64.3, P<0.05).³⁰ The second RCT (30 women) found that more women taking clonidine reported reduced flushes at 8 weeks (12/15 v 5/14, P<0.04).⁴⁰ Psychological symptoms: We found no RCTs. Quality of life: We found no RCTs.

Harms
The two RCTs found no significant difference in the incidence of unwanted effects between placebo and active treatment groups. ^{39 40}

Comment
None.

Benefits
We found no systematic review. Vasomotor symptoms: We found no RCTs evaluating testosterone alone in women with menopausal symptoms. We found one RCT (93 postmenopausal women) comparing oestrogen alone and oestrogen plus methyltestosterone. This concluded that addition of a small dose of methyltestosterone reduced the dose of oestrogen needed to control menopausal symptoms.⁴¹ Urogenital system: We found two RCTs, one in 40 women and one crossover study in 53 women. Both found benefit from exogenous testosterone on self reported sexual enjoyment, desire, and arousal. ^{42 43} Psychological symptoms: We found no RCTs. Beneficial effects of therapy on quality of life: We found no RCTs.

Harms
We found no evidence from RCTs or other controlled studies on the incidence of androgenic adverse effects with testosterone.

Comment
None.

Benefits
We found no systematic review or RCTs that specifically addressed the effects of antidepressants on menopausal symptoms or quality of life in menopausal women.

Harms
We found no evidence on adverse effects in postmenopausal women. Antidepressants as a group can cause many central nervous system adverse effects, including sedation and agitation, as well as urinary and vision problems, liver dysfunction, and cardiac dysrhythmias.⁴⁴

Comment
None.

	Footnotes

   Competing interests: JR has been sponsored to attend conferences by Organon, Solvay Healthcare Ltd, Wyeth, Novo Nordisk, and Janssen-Cilag and has received research funding from Organon and consultancy fees from Organon, Wyeth, and Janssen-Cilag. EPM has been sponsored to attend conferences and has received speaker's fees from Eli Lilly, Organon, and AstraZeneca.

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