Menopause: Drug Therapy

Therapeutic target

Improvement of climacteric symptoms and, if present, therapy of osteoporosis (bone loss).

Therapy recommendations

Therapeutic hormone replacement therapy (HRT) is indicated for:

  • Moderate to severe menopausal symptoms.
    • Women with vasomotor symptoms (e.g., hot flashes, sweats) should be offered HRT [S3 guideline].
  • Urogenital or vaginal atrophy/vaginal dryness (see estriol below) [If this is the only indication for therapy, vaginal estrogen therapy (estrogen vaginal therapy) should be offered exclusively].

A prerequisite for therapeutic hormone replacement therapy is that the complaints are considered burdensome by the patient, so there is a clear indication, and there are no contraindications:

  • Nonhysterectomized patients (i.e., patients with a uterus) may receive combined hormone therapy with estrogens and progestins (combination therapy), i.e., at least 10-, preferably 14-day progestin applications per month of treatment. The progestin supplement serves to protect (protect) the endometrium (endometrium) from the stimulating effect of estrogen (prevention of endometrial cancer / uterine cancer).
  • Hysterectomized patients may receive estrogen therapy (estrogen monotherapy).

Preventive hormone replacement therapy may be indicated for:

* In asymptomatic urogenital atrophy, the use of moistening, lubricants alone or together with vaginal estrogen therapy should be offered [S3 guideline]. Premature ovarian insufficiency (POI).

Women with POI should be educated about the importance of hormonal treatment with hormone replacement therapy (HRT) or combined oral contraceptives (OC) at least until natural menopausal age, unless there is a contraindication to HRT or combined OC [S3 guideline]. Contraindications to hormone replacement therapy.

  • Breast carcinoma/breast cancer (including condition after)Hormone replacement therapy may increase the risk of recurrence (recurrence of disease) after treated breast carcinoma [ESC S3 guideline].
  • Endometrial carcinoma/uterine cancer (also condition after)The risk of hormone replacement therapy after treated endometrial carcinoma has not been adequately studied [S3 guideline].
  • Endometrial hyperplasia (circumscribed or generalized increase in volume (hyperplasia) of the endometrium).
  • Previous idiopathic and acute venous and arterial thromboembolism (ischemic cerebral insults/stroke, myocardial infarction/heart attack).
  • Liver disease, as long as the relevant liver enzymes are elevated.
  • Unexplained vaginal bleeding (bleeding from the vagina).

Other indications

  • Review of the indication for hormone replacement therapy (HRT) should be performed three months after initiation of therapy and at least annually thereafter.
  • For high-risk patients, transdermal HRT is preferable.
  • Non-hormonal alternatives may be used if contraindications to HRT are present.
  • Women should be advised before starting treatment that vasomotor symptoms (e.g., hot flashes, sweats) may recur after stopping hormone replacement therapy.

Current state of knowledge

The results of known studies presented below indicate that an individual risk-benefit analysis must always be performed by your physician – together with the patient: On July 17, 2002, the American Medical Journal published a study on the effects of long-term treatment of postmenopausal women with estrogen/progestin preparations. This study – called the “Women’s Health Initiative” (WHI) – had to be stopped prematurely because the interim analysis of the data collected up to that point already showed a significantly increased rate for breast carcinoma (breast cancer), coronary heart disease (CHD), apoplexy (stroke) and thrombosis/lung embolism compared to the placebo group. These results were confirmed by the British One Million Women Study with regard to breast cancer risk. The risk of disease and mortality (“risk of death”) was even higher than in the American study, according to an evaluation in the Lancet. The Collaborative Group on Hormonal Factors in Breast Cancer points out that when hormone replacement therapy (HRT) is used for more than five years, the risk of breast cancer may be increased for ten years or more after discontinuation. However, the Womeńs Health Initiative (WHI) study and the One Million Women Study also showed that hormone replacement therapy resulted in a reduction in femoral neck fractures-10 fractures (broken bones) versus 15 fractures in the untreated group. The U. S. Preventive Services Task Force concluded the following in 2005: Despite the beneficial effects of appropriate hormone replacement therapy on bone density, with a reduced risk of fracture (bone breakage) and reduced risk of developing colon cancer (colon cancer), the risks such as increased risk of breast cancer and venous thromboembolism (VTE), apoplexy (stroke), cholecystitis (gallbladder inflammation), dementia, and possibly coronary artery disease (CAD; coronary artery disease) outweigh the benefits. According to the current state of science [7,8, 9], hormone replacement therapy (HRT) only slightly increases the risk of cardiovascular events such as coronary heart disease (CHD). The decisive factor is when hormone replacement was started after menopause (so-called “window of opportunity”). The risk of cardiovascular disease and death decreases if the start of therapy is shortly after menopause or before the age of 60. If the women were older than 60, they no longer benefited from hormone replacement therapy. Furthermore:

  • The risk of cerebral insult (stroke) and venous thromboembolism (here, especially in the first year of use) is increased. This does not seem to apply to transdermal (“through the skin“) application of estrogen.
  • The risk of cholelithiasis (gallstones) is already increased in the initial phase, especially in obese women and after previous biliary disease the gallbladder carcinoma risk is not increased.
  • The risk of developing vascular (“vessel-related”) dementia is increased in women who receive combination therapy beyond the age of 65 years.
  • The risk of developing AD is significantly reduced in women with early initiation of hormone replacement therapy (within five years of the onset of menopause) and duration >10 years. However, these long-term assumptions contradict general therapeutic practices, as low as possible, as short as necessary.A Finnish case-control study examining Finnish women receiving hormone replacement after menopause showed an increased risk of developing AD later. Here, vaginal application appears to be harmless:users of estrogen monopreparations showed an odds ratio of 1.09, which was significant with a 95% confidence interval of 1.05 to 1.14; for women who had used estrogen-progestin combinations, the odds ratio was 1.17 (1.13 to 1.21); thus, the absolute risk is minimal.
  • Malignancies with increased risk of disease:
    • Breast carcinoma/breast cancer (mainly with combination therapy (estrogen-progestin therapy), less with isolated estrogen therapy; the risk increase was shown with estrogen-progestin therapy from a use time of more than five years; an analysis of WHI (Womeńs Health Initiative) data showed an increase in breast cancer rates with early postmenopausal use even with less than five years of treatment; with estrogen therapy, the mean risk was decreased after a mean use time of 5.9 years: When discussing the risk of breast cancer, it must be taken into account that hormone application is not responsible for the development of breast cancer, i.e., it does not have an oncogenic effect, but merely accelerates the growth of hormone receptor-positive carcinomas. After an intake period of more than five years, the risk of breast cancer increases by less than 0, 1 % per year (< 1.0 per 1,000 women per intake year). However, the risk increase is lower than that due to regular alcohol consumption and obesity. CONCLUSION: When combined hormone replacement therapy is used for longer than five years, a careful benefit-risk assessment must be made.
    • Endometrial cancer / endometrial cancer (in non-hysterectomized postmenopausal women (women in postmenopause with a uterus), there is already a 5-fold risk of disease under estrogen monotherapy after 3 years of intake, and a 10-fold risk after 10 years. The simultaneous application of a progestogen in a transformation dose (conversion dose) for the endometrium (uterine mucosa) of at least twelve days in the month of application or continuously is therefore obligatory. It is also possible to insert a levonorgestrel coil (off label use). If progesterone is used, this must be applied vaginally (“through the vagina”) (zuführt), since the oral or transdermal (“through the skin“) application seems to be insufficient for the transformation of the endometrium).
    • Ovarian cancer/ovarian cancer (The study situation is unclear. If there is any risk at all, it is currently considered rare to very rare. However, it is recommended in the presence of a family disposition to the possible risk).

    Malignancies with likely reduced risk of disease:

    • Colon and rectal (colon and rectum) cancers are likely to be lowered. This needs to be followed by further studies (7, 8, 9).

Furthermore, hormone replacement therapy (HT) should not be given if the patient has previously had a hormone-dependent malignancy. However, publications in prestigious journals such as Science suggest that individualized hormone therapy still has its importance. The German Society of Gynecology and Obstetrics, the Professional Association of Gynecologists and numerous other professional societies formulate in an updated recommendation: “According to current data, it is to be expected that with early substitution – at the age of less than about 60 years – , while avoiding long-term estrogen deficits, the benefits of indicated hormone replacement therapy (HRT) usually outweigh the risks for women not burdened with special risk factors or pre-existing diseases. In the meantime, the authors of the WHI study in the “New England Journal of Medicine” have corrected the validity of their own study: In women between 50 and 59 years of age, in addition to the sustained elimination of hormone deficiency symptoms, a lower number of bone fractures, a reduction in the rate of diabetes and deaths in general can be observed. An evaluation of the Women’s Health Initiative (WHI) follow-up study of estrogen replacement in postmenopause demonstrated that the increase in breast cancer and cardiovascular disease that prompted early discontinuation of the two randomized trials in 2002 and 2004 did not increase the mortality risk (risk of death) of participants in the long term. The U.S. Preventive Services Task Force (USPSTF) has continued to oppose the use of post-menopausal hormone replacement therapy to the extent that the purpose is prevention of chronic disease. Conclusion Hormone replacement therapy should be used only in cases of severe menopausal symptoms, climacteric praecox, and urogenital or vaginal atrophy (in this case, only vaginal estrogen therapy, preferably with estrus). In principle, however:

  • Hormone replacement therapy should be used only as long as necessary and at the lowest possible dose.
  • Hormone therapy should not be performed after hormone-dependent tumor diseases.

Further notes

  • A Finnish registry study showed that women who stopped therapeutic hormone replacement therapy (HRT) before age 60 had an increased risk of cardiac or cerebrovascular death within the first year after discontinuationFor women who were already older than 60 years at HRT discontinuation, the risk of cardiac or cerebrovascular death was either decreased or unchanged compared with the comparison collectives

Modes of action

Estrogens Estrogen hormone deficiency causes, among other things, lipoprotein(a) levels to increase significantly at menopause. The reason for the increase is the discontinuation of estrogens: estrogen replacement therapy causes a dose-dependent reduction of lipoprotein (a) by up to 20% and of LDL cholesterol by 10%, with a simultaneous increase in HDL cholesterol. As an undesirable side effect of estrogen hormone replacement therapy, it causes an increase in triglycerides of up to 25%! The side effects described above are less pronounced with transdermal therapy. Tibolone has estrogenic, androgenic, and gestagenic properties. Progestogens The effects of progestogens on lipid metabolism and hemostasis (“hemostasis”) interact with estrogens: Lipid metabolism Synthetic progestins, for example, reduce the HDL cholesterol-increasing effect of estrogens; androgen-acting 19-nortestosterone derivatives even cancel this or lead to a reduction in HDL cholesterol. The effect of hypertriglyceridemia (lipid metabolism disorder with elevated triglycerides) caused by estrogens is reversed by 19-nortestosterone derivatives. Progestogens have no effect on LDL cholesterol. The positive lipoprotein (a) effect of estrogens is not weakened by progestins and is even enhanced by 19-nortestosterone derivatives. For effects of natural progesterone on lipid metabolism (fat metabolism), see below under “Combination preparations”. Hemostasis (hemostasis) Progestins inhibit the effects of estrogens on factor VII, pasminogen activator inhibitor 1 /(PAI-1), and fibrinogen.

Active ingredients (main indication)

Monopreparations

  • 17ß-estradiol ester
  • Micronized 17ß-oestradiol ester
  • Conjugated estrogen
  • Estriol

Synthetic estrogen mimetics

  • Tibolone

Combination drugs

The demands of M. Whitehead et al. should always be taken into account: for the reliable prevention of endometrial hyperplasia, a 12-day progestogen phase (e.g. as transdermal therapy with a natural progesterone – Utrogest 0.5-1 g /die) is necessary: The risk of endometrial cancer (cancer of the endometrium) continues to decrease with the addition of an effective progestogen for 12 days or longer with increasing treatment duration. The same is true for beneficial effects at the serotonin receptor.

SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin-norepinephrine reuptake inhibitors)

  • SSRIs, SNRIs, and gabapentin (drug in the anticonvulsant group) have potential benefits for reducing hot flashes.

Alternative therapies

From the point of view of reducing hot flashes, sweats, and sleep disturbances, herbal preparations (phytotherapy) are much discussed and frequently used as an alternative to hormone therapy, either in case of rejection by an affected woman or in case of contraindications (e.g., breast carcinoma) or fear of adverse effects (e.g., thrombosis, embolism). Relevant meta-analyses and systematic reviews available to date have led to the statements reflected in the guidelines on hormone therapy in the “Alternative Therapy” chapter:

  • Isoflavone-containing dietary supplements of soy and red clover or a diet rich in phytoestrogens do not reduce hot flashes or do so marginally, if at all.
  • Isoflavones can be used for vasomotor symptoms (e.g., hot flashes, sweats) [S3 guideline].
  • For mild hot flashes and sweating, a therapy trial with isoflavones or Cimicifuga is possible. The effect cannot be predicted individually. In severe vasomotor symptoms, a sufficient therapeutic effect is not expected.
  • In the presence of contraindications (contraindications) to hormonal therapies and the need for therapy, SSRIs (selective serotonin reuptake inhibitors) and gabapentin, an antiepileptic drug, may be considered as individual therapy trials. However, both substances are currently not approved for this indication. It is therefore necessary to provide medical justification based on the risk-benefit assessment and to inform the patient of the facts (“off-label use“; use outside the indication areas or the group of people for which the drugs are approved by the drug authorities). Note: Serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), clonidine, and gabapentin should not be routinely offered as first-line agents for vasomotor symptoms [S3 guideline].
  • There are currently insufficient data on long-term safety for all alternative therapies.

Herbal products (phytotherapeutics).

  • Some herbal active ingredients, which are contained, for example, in lady’s mantle, lemon balm or monk’s pepper, are used against general menopausal symptoms. Their effect is rather weak. Long-term consequences of a hormone deficiency can be neither prevented nor treated by these medicinal plants.
  • Cimicifuga racemosa (American – tall – perennial Christopher’s wort, woman’s root, rattlesnake herb, North American snake root, snake herb consumptive root, silver primrose, grape-shaped blackroot, black cohosh, bugweed). The root extracts are used against climacteric symptoms [S3 guideline]. They contain triterpene glycosides that exert an estrogen-like effect, but are not estrogen-like in structure and do not bind directly to estrogen receptors. The extracts are therefore considered hormone-free, in contrast to phytoestrogens. However, like these, they act as estrogen receptor modulators (SERMs). In Germany, they are offered as medicinal products, unlike the phytoestrogens, which are on the market as dietary supplements. Important effects of Cimicifuga on the:
    • Breast tissue especially in the aspect of mammary carcinoma (breast cancer) or condition after mammary carcinoma: The current data does not allow a definitive statement on risk or prevention. Therefore, its use should be considered very critically, especially because only a small therapeutic effect is expected, as:
      • According to current data, with an unclear mechanism of action, possible effects of Cimicifuga on mammary gland tissue cannot be ruled out and.
      • Meaningful clinical studies on the safety of Cimicifuga in breast carcinoma patients are lacking.
    • Endometrium (endometrium) especially in the aspect of the development of corpus carcinoma (endometrial cancer):
      • Estrogenic effects of Cimicifuga on the endometrium are not known from practical use and individual observational studies.
  • Phytoestrogens Phytoestrogens are divided into three groups:
    • Isoflavones (main metabolites are: daidzein, genistein, formononetin): they are contained in: Soy, or soy products (eg, tofu), beans, fruits, vegetables.
    • Lignans (main metabolites are enterolactone, enterodiol): they are contained in: Berries, whole grains, flaxseed.
    • Coumestanes (main metabolite is coumestrol): they are contained in: Alpha sprouts, red clover

    Phytoestrogens are estrogen-like in their chemical structure. They bind to the estrogen receptors (alpha and beta receptors) and therefore act as SERMs (estrogen receptor modulators). However, they have only 0.1 – 0.01% of the effect of endogenous estrogens.

  • Plant extracts are offered in Germany as dietary supplements in contrast to cimicifuga root extracts, which are marketed as drugs. Effect of phytoestrogens on the:
    • Breast tissue especially in the aspect of mammary carcinoma or condition after mammary carcinoma: The current data do not allow a definitive statement on risk or prevention. Although only a small therapeutic effect is expected, the following beneficial effects are worth mentioning:
      • Epidemiological studies (Japan) indicate a possible reduction in the risk of breast cancer by isoflavone-rich diet.
      • the possible preventive (precautionary) effect among premenopausal women (before menopause) seems to be greater than among postmenopausal women (after menopause)
      • The mammographic density of the mammary gland tissue is not affected under isoflavones
      • Changes in proliferation markers under isoflavones are not detectable
    • Endometrium (endometrium) especially from the point of view of the development of corpus carcinoma (malignant disease starting from the endometrium): according to current data, at a dosage of 100 mg isoflavones/die for one year (long-term studies are lacking) in postmenopause, there is no effect on
      • Histological (fine tissue) changes.
      • Vaginal sonographic increase in endometrial thickness.
  • A meta-analysis was able to establish the following effects for phytoestrogens:
    • Reduction in the frequency of hot flashes; compared with placebo, reduction in the number by an average of 1.3 attacks daily
    • Decrease in vaginal dryness; compared with placebo, by an average of 0.3 points on a scale of 0 to 3 (highest severity)

Phytotherapeutics

Active ingredients Dosage (root extracts)
Cimicifuga racemosa 6-7 mg/d (max. 12 mg/d)
Soy or red clover supplements They usually contain 20-40 mg of isoflavones 40-80 mg/d (max. 120/d ?)

Dietary intake of phytoestrogens in Western Europe is estimated at a maximum of 2 mg/day. In Asian countries, where soy is a staple food, about 50-80 mg/day of isoflavones are consumed in the diet. To reach a daily intake of 50 mg of isoflavones one has to consume about 500 ml of soy milk. Soybeans contain the highest concentration (3-4 mg isoflavone/g protein). Processed soy products such as tofu or soy flour contain about 2 mg isoflavone/g protein. It should be noted that the content of phytoestrogens in foods can vary greatly.

Supplements (dietary supplements; vital substances)

Suitable dietary supplements should contain the following vital substances:

In the presence of insomnia (sleep disorders) as a result of menopausal symptoms, see below Insomnia/Medicinal Therapy/Supplements. Note: The listed vital substances are not a substitute for drug therapy. Supplements are intended to supplement the general diet in the particular life situation.

Medicines

If there are pronounced vasomotor (“relating to the movements of the blood vessels“) climacteric symptoms and if the quality of life is significantly reduced, the following drugs may be considered as a therapeutic attempt in the case of contraindications (contraindications), e.g., in or after mammary carcinoma (breast cancer) and rejection of the above-mentioned possibilities of influence:

Antidepressants from the SSRI group (selective serotonin reuptake inhibitors): In short-term studies, they reduce hot flashes by 50-60%. Comparative studies with estrogen preparations are lacking, so no statement can be made about the relative effectiveness with regard to the reduction of hot flashes.

Menopause after breast carcinoma

The HABITS study clearly showed a higher risk of recurrence when carcinoma patients continued to take combined hormone therapy. Alternatively, antidepressants from the selective serotonin reuptake inhibitor (SSRI) group can be used in such cases. These drugs significantly reduce the frequency and frequency of hot flashes. The SSRIs paroxetine, citalopram and escitolapram and the selective serotonin reuptake inhibitor (SNRI) venlafaxine seem to be the most effective.