Summary

With the population ageing which happens in many advanced societies, the problems associated with menopause are important issues. Management options include medical and non-medical measures. Medical measures, which include hormone replacement therapy (HRT), tibolone and raloxifene have been reviewed in Part I in a previous article. The alternatives include phyto-oestrogens, androgens, bisphosphonates, calcitonin, parathyroid hormone, calcium and vitamin D, omega-3, statins, beta-blockers and angiotensin-converting enzyme inhibitors. Some of these alternatives are discussed in this article.

摘要

很多發達國家社會不斷老齡化，絕經相關的問題正成為重要的課題。治療包括藥物和非藥物兩類。激素替代療法(HRT)、替勃龍(tibolone)和雷洛昔芬(raloxifene)在內的藥物手段已經在前一期討論過。其他治療絕經的替代藥物有植物雌激素、雄激素、雙膦酸鹽類藥物、降鈣素、甲狀旁腺激素、鈣加維生素D、omega-3、他汀類藥物、-受體阻滯劑和血管緊張素轉換抑制劑。本文對其中一些替代藥物加以討論。

---

Introduction

Menopause is a significant risk factor for osteoporosis (leading to vital fractures), cardiovascular diseases (including ischaemic heart disease and cerebro-vascular accidents) and malignancies. Other than menopause, other risk factors for osteoporosis leading to fatal fractures include: ageing, extreme bodyweight, low bone density when young, nutritional deficiency (e.g. calcium and vitamin D), being female, personal history of previous fracture or family history of spontaneous fractures, prolonged steroid consumption; smoking, prolonged immobilization, and being Caucasian.

To minimize the risk and have a better quality of life, medication and healthy lifestyle are always important for all menopausal ladies, especially for the high risk group. The choice between HRT, tibolone and raloxifene has been discussed in Part I in a previous article. The non-HRT alternatives which include phyto-oestrogens, androgens, bisphosphonates, calcitonin, vitamin D and calcium, parathyroid hormone (PTH), and omega-3 are discussed in this article.

Phyto-oestrogen

Non-prescription remedies are becoming increasingly popular in the consumer market. One of the reasons is they can be bought over the counter without a prescription. Another reason for the increasing popularity is that: the values of these products are heavily promoted by the commercial sector, manufacturers, and to those who have resistance to "prescribed medications". Phyto-oestrogens are a large family of products derived from plant. It is believed that these products possess various degrees of oestrogen activity. Food or food supplements containing phyto-oestrogens are often seen advertised as a safe alternative to HRT in the management of menopausal problems.

Soybean is a natural dietary source of isoflavones, which has oestrogen-like properties. Some preliminary studies suggest an antiosteoporotic effect of isoflavones. Isoflavones may increase HDL and decrease LDL concentrations and these effects may be beneficial in the prevention of arteriosclerosis. Therefore, especially with the recently published findings of the Heart and Estrogen/Progestin Replacement Study (HERS) I/II and the Women"s Health Initiative (WHI) studies, soybeans have been promoted as a replacement for HRT. Also there is no evidence to suggest that consumption of soybean may increase venous thromboembolic disease or stroke. However, only limited and flimsy data are available in this area. Despite there are some short-term studies suggesting that soybean may reduce bone loss in postmenopausal women, the effects have been noted primarily only at the spine, and longer-term or elegantly designed studies are not available. The suggestion that the consumption of soybean may decrease cancer (e.g. colon) risk is only speculative. The use of soybean and red clover derived isoflavones has not been shown to have beneficial effects on the urogenital tract, including the vagina.

Cimicifuga racemosa extracts are traditionally used for the treatment of climacteric complaints. Again there is only some preliminary suggestion that the unknown compounds in Cimicifuga racemosa extracts may help the climacteric symptoms and may also have antiosteoporotic effects.¹

There has been no good study performed on phyto-oestrogen looking at the various aspects of the postmenopausal women"s health and the results are conflicting and difficult to interpret. Understanding the intrinsic defects in studying most natural herbs, proper studies are going to be difficult (e.g. different sources from different locations, different composition with different timing of the season when the plants are harvested, the lack of knowledge of the active ingredient, the lack of standardisation of the preparations used, its minimally effective doses, the large individual variability of metabolism of precursors introduced etc). That may also explain why the companies producing these supplements are not interested in investing in proper long-term research from which they will not exclusively benefit. The worst thing is, without proper study, the possible side effects would never be known. This is certainly of concern when all "natural products" are claiming to be free of "side-effect" while in fact, this has never been properly studied (which definitely does not equate to side-effect free).

As many of the phyto-oestrogens are marketed as "natural products", many kinds of advantages have been claimed and these claims escape the jurisdiction of the pharmaceutical verification. This has an extremely important health cost implications as unproven efficacy of the products means huge amount of national resource is spent without justification. It is difficult for the physician to advise patients on this matter.² Large scale, better designed and long-term studies are essential before we should promote the use of phyto-oestrogen alone as an acceptable management for menopausal ladies. All health professionals have the ethical obligations to make sure the exact picture be discussed with the patients to avoid confusion leading to wastage of money or even worse, the risks of unknown side effects of these "natural products". At the present moment, however, it may be reasonable to suggest the consumption of some but not obsessionally excessive amount of soybean in the diets for menopausal women.³

Androgens

Menopause and the years leading to the menopausal transition are associated with significant decline in sex steroid levels. In females, half the circulating androgens come from the adrenal glands and half from the ovarian stroma. There are 3 forms of clinically relevant androgens, namely dehydroepiandrosterone (DHEA) and its sulphoconjugate DHEA-sulphate (DHEA-S), and testosterone (T). DHEA-S is a pro-hormone produced almost exclusively from the zona reticularis (innermost zone) of the adrenal cortex. DHEA-S has no identifiable receptor in the cells. It has to be converted in the cell to T or testosterone"s potent derivative, dihydro-testosterone (DHT) to express its androgenic functions. This involves the removal of the sulphate by the enzyme, steroid sulphatase to form DHEA, and then a conversion to androstenedione, T and finally DHT. DHT then interacts with the signal transduction systems of the androgen receptor (AR). DHEA-S concentration starts to increase from around age 7 to 8 years old. Its increase during that period may be associated with the adrenarche leading to the development of pubic and axillary hairs, sexual desire, increased muscle growth and strength, increase bone mass and linear growth, and maturation of immune system. Its level reaches the peak at around 20 to 30 years of age, and declines from 40 to 50 years of age onwards. These may be related to the loss in the zona reticularis cell mass and apoptosis. Clinically this may also be associated with the "reversed adrenarche"; that is, loss of pubic and axillary hairs, loss of muscle and bone mass, decreased libido, loss in height and decreased immune defense.

In contrast to the abrupt drop in oestrogens at the time of menopause, a gradual fall in the circulating T and the adrenal pre-androgens occurs with increasing age. Their accelerated decrease occurs in the years preceding menopause. At menopause, the ovaries shrink to half of the size in reproductive age. They change from follicle-dominant oestrogen producing organs to stroma-dominant androgen secreting organs. Therefore the decline of circulating T in natural menopause is much more gradual. It is also thought that the elevated circulating LH level in menopause helps to sustain the T secretion. However, after surgical menopause, the T level may abruptly drop by 40 to 50%. The decreasing levels of androgens may have a significant impact in the quality of life in perimenopausal and menopausal ladies. Libido, vasomotor symptoms, bone structure, muscle mass, mood and well-being, may all be affected. Recently, studies suggest about 10% of natural menopausal women have decreased libido. There may be a place for using androgen replacement for women who have undergone premature or surgical menopause and also in natural menopause experiencing premenopausal loss of libido from diminished free testosterone.⁴

In the past, the therapy is usually empirical. Methyltestosterone 1.25mg/day, coupled with conjugated oestrogens 0.625mg (Estratest) for 16 weeks, in a randomized controlled trial (RCT) suggests significant improvement of libido.⁵ Testosterone implant (50 to 100mg) has been implanted subcutaneously every 3 months and has shown to increase T level for 2 to 4 months and significantly improve libido in a prospective study.⁶ Testosterone gel has also been used but very limited data is available to validate its efficacy. Recently, the FDA has declined the application of Intrinsa (a testosterone patch claiming improvement of females" decreased libido) by Procter & Gamble, because the proof of efficacy is lacking. The decision is not surprising if we believe that the causes for reduced sexual desire are multifactorial and not totally androgen related. Apparently Procter & Gamble is going to submit the results of a much bigger Clinical phase III trial to FDA again (about 5,000 instead of the 1,100 menopausal women in the initial application).

Bisphosphonates

Bisphosphonates⁷ are potent bone resorption inhibitors. They are widely used both in cancer patients and in the prevention and treatment of spinal and peripheral osteoporotic fractures. Randomized, double-blind, controlled studies have shown that treatment with risedronate reduces the risk of vertebral fracture in postmenopausal women with established vertebral osteoporosis. They also show that the drug decreases the risk of non-vertebral fractures in women with osteoporosis. Of the drugs that have been approved for the prevention or treatment of osteoporosis, the bisphosphonates (risedronate and alendronate) are effective in reducing the risk of vertebral and nonvertebral fractures. Risedronate has been shown to reduce fracture risk within one year in postmenopausal women with osteoporosis and in patients with glucocorticoid-induced osteoporosis.

Oral bisphosphonates are usually well tolerated. Contraindications are rare. But some may experience gastric and oesophageal symptoms. The intestinal absorption is only 0.5-1% and may be reduced with food. Intravenous bisphosphonate may be considered in some selected cases, e.g. those with severe gastrointestinal side-effects or elderly patients where compliance is a problem. However, acute renal failure has been reported. Prolonged intravenous infusions may also cause thrombosis or infections. Intravenous bolus injection of some bisphosphonate (e.g. the highly potent, nitrogen-containing bisphosphonates such as ibandronate, zoledronic acid or pamidronate) may be considered as an alternative to intravenous infusion in this situation. These potent bisphosphonates, unlike other lower potency bisphosphonates, can be administered effectively as only a small dose is required at long intervals between injections. Zoledronic acid, when administered intravenously, not only can prevent bone loss, but also can increase the bone mass density (BMD) in prostate cancer patients with bone metastasis. Therefore, intravenous zoledronic acid or pamidronate may be considered in the treatment of osteolytic bone metastases in cancer (e.g. breast).⁸

When compared with HRT or SERM (Selective Estrogen Receptor Modulator), bisphosphonates usage is not associated with thrombo-embolic risks. They do not however provide other systemic benefits other than bone protection (e.g. reduction of dyslipidaemia by both HRT & SERM, control of vasomotor symptoms by HRT, or the apparent breast cancer reduction of raloxifene). It can be used in women when HRT is contra-indicated or raloxifene is not proven safe (e.g. breast cancer, thrombo-embolism).

Calcitonin

Extracted from salmon, calcitonin is a naturally occurring peptide which acts via specific receptors to strongly inhibit osteoclast function. Historically, calcitonin was administered as a parenteral injection, but the intranasal formulation is now the most widely used because of its improved tolerability.

Some controlled trials have reported that calcitonin leads to a short-term increase in bone density at the lumbar spine (1%-2% increase of BMD after 1 year with 200 IU daily).⁹ In the Prevent Recurrence of Osteoporotic Fractures (PROOF) study, a 5-year double-blind, randomised, placebo-controlled trial, salmon calcitonin nasal spray, when used at 200 IU/day, reduces the risk of vertebral fractures by 33% (relative risk [RR] = 0.67; 95% CI 0.47, 0.97; p = 0.03). Increased dosage of 400 IU/day dosages did not significantly reduce vertebral fracture risk. Effects on nonvertebral fractures were not significant (RR = 0.80; 95% CI 0.59, 1.09; p = 0.16). Evidence is accumulating that calcitonin diminishes bone pain in osteoporotic vertebral fractures. It may also be used in men with idiopathic osteoporosis. The use of calcitonin in corticosteroid-induced osteoporosis remains controversial. Long-term and more elaborate studies are necessary to confirm all these reports.¹⁰

Given long term through inhalation, there is concern about the efficacy in absorption through the nasal mucosa. As the protein is from another species, antigenic stimulation is possible.

New approaches are currently being investigated to enhance the bioavailability and effects of calcitonin, including oral, pulmonary, and transdermal routes of administration, and novel allosteric activators of the calcitonin receptor. At this moment, this might not therefore be the ideal first-line drug for use in menopausal women. It may be used temporarily where HRT is contra-indicated or raloxifene is not proven safe (e.g. breast cancer, thrombo-embolism), or if pain is a significant component of the osteoporosis or fracture.¹¹

Vitamin D and calcium

A panel of authorities in the field of calcium research was appointed by the North American Menopause Society (NAMS) to review the role of calcium in peri- and postmenopausal women. Although calcium is not as effective as antiresorptive agents (e.g. oestrogen, selective oestrogen-receptor modulators, or bisphosphonates) on its own, together with adequate Vitamin D, they may become the adjuvant. Adequate intake of calcium may also be associated with other beneficial effects with regard to hypertension, colorectal cancer, obesity, and nephrolithiasis, although the extent of those effects and mechanisms involved need much more research. It is thought that at least 1,200 mg/day of calcium is required for most women. However excessive dose (more than 2,500 mg/day) is not to be taken and in fact, may have undesirable side-effects. Daily intake of 400-600 IU of vitamin D daily is also suggested to make sure there is adequate calcium absorption. Vitamin D absorption can be achieved either through sun exposure, diet or supplementation.^12,13

Parathyroid hormone

HRT, SERM, and bisphosphonates all act mainly by minimizing bone resorption. Only parathyroid hormone (PTH), when given intermittently, is supposed to increase bone deposition. They stimulate osteoblast accumulation and bone formation in three ways via signals from the Type 1 PTH/PTH-related protein (PTHR1) receptors on proliferatively inactive preosteoblasts, osteoblasts, osteocytes and bone-lining cells. The receptor signals inhibit the proliferatiion in preosteoblasts and promote their maturation to osteoblasts. Then the osteoblasts would secrete several factors to stimulate the extensive proliferation of osteoprogenitors without PTHRI receptors, stimulate the reversion of bone-lining cells to osteoblasts, and extend osteoblast lifespan and productivity by preventing them from apoptosis (i.e., programmed cell death).¹⁴

PTH is now commercially available as a genetically engineered 34 amino acid protein with the designation teriparatide or recombinant human (h)PTH-(1-34). PTH is the first anabolic osteoclastic medication that has been approved for use in the US (by FDA in 2001) and Europe for the treatment of postmenopausal osteoporosis. Teriparatide has been shown to considerably increase cancellous and cortical bone mass, bone microstructure, prevent fractures, when administered subcutaneously at a daily dose of 20 micrograms for no longer than 2 years to patients with osteoporosis. These are additional benefits that cannot be provided by other antiresorptive therapies.¹⁴

A recombinant DNA preparation with all 84 amino acids of the native PTH molecule is in clinical trials. These PTH preparations are self-administered daily injections, and it is approved for women and men at high fracture risk, including patients with prevalent fractures, low bone mass, and multiple risk factors. It has been shown to reduce vertebral and non-vertebral fractures. It increases bone mass, by stimulating bone formation on all bone surfaces and is referred to as an osteoanabolic agent. PTH is mostly used in patients with fractures, but can be used in patients who are at high risk for fractures (severely osteoporotic). Previous treatment with alendronate may impair the anabolic response of PTH preparations. Patients who have Paget's disease, prior radiation therapy to the skeleton, as well as children and young adults with open epiphyses, and who are at higher risk for osteosarcoma should not be given PTH. Similarly, patients with hypercalcaemia and hyperparathyroidism also should not receive this drug.¹⁵ The theoretical risk of association with osteosarcoma and other long term side-effects need to be studied carefully.¹⁶

Omega-3 fatty acids

Eicosanoids, are endogenous hormones locally produced in tissues. There is some suggestion that they are important in the prevention and treatment of some women diseases. Omega-3 fatty acids (omega-3 FA) are constituents of the membranes of all cells in the body and are precursors of the eicosanoids. Imbalance between anti-inflammatory, vasodilator eicosanoids derived from omega-3 FA and proinflammatory, vasoconstrictor eicosanoids derived from omega-6 FA has been postulated as one of the possible mechanisms for dysmenorrhea. Therefore, it is suggested that increased omega-3 FA intake may help dysmenorrhoea by decreasing the amount of omega-3 FA production in cell membranes. Some other obstetrics and gynaecological conditions (e.g. pre-eclampsia, subfertility) have also been postulated to be related to a disturbed prostacyclin/thromboxane ratio. Increased omega-3 FA may help to prevent these conditions by increasing uterine blood flow with the increased prostacyclin/thromboxane ratio. By altering the balance of different eicosanoids it is also hoped that omega-3 FA taken during pregnancy may reduce the risk of premature birth and thus may increase the birth weight. Other postulated advantages of taking omega-3 FA during pregnancy and breast feeding include better brain development in children, reduce risk of developing pre-eclampsia and postpartum depression. Other postulated advantages in gynaecology include the management of menopausal problems, postmenopausal osteoporosis, and breast cancer.

Omega-3 FA is said to reduce the triglycerides level in blood. Therefore, this may have an impact on the prevention of cardiovascular diseases in menopause, especially in women receiving hormone therapy whereby the blood triglycerides level are also increased.

Well-designed proper randomised controlled trials are required before omega 3 can be medically recommended to menopausal ladies as part of management. Besides, there is a suggestion that the omega-3 FA preparation should have an appropriate antioxidant content so that it does not induce lipid peroxidation, and its content of dioxin and polychlorinated biphenyls (PCBs) should be well below the established safe limit.¹⁷

Effects of smoking

In the Women"s Health Initiative (WHI), 50% of the 8,500 women on HRT were smokers or ex-smokers. Smoking affects pituitary, thyroid, adrenal, testicular and ovarian function, calcium metabolism and the action of insulin. The risk and severity of Graves" hyperthyroidism and ophthalmopathy, osteoporosis and subfertility may be increased. Smoking may also be involved in the development of insulin resistance and Type 2 diabetes mellitus.¹⁸ It has been suggested that smoking may reduce or alleviate the efficacy of orally administered oestrogens. It may reduce the beneficial effects of oestrogen on vasomotor and urogenital symptoms, the lipid-lowering effects (i.e., by reducing cholesterol) and the prevention of osteoporosis. The reduction of oestrogen action is mainly caused by increased liver clearance, which may be dose-dependent. Failure of therapeutic action can be counteracted by increasing the dose of oestrogen. However, this may not be desirable as it may increase the potentially mutagenic oestrogen metabolites. These metabolites may be associated with a higher risk of oestrogen-dependent cancers (e.g. breast). Another way to increase the efficacy of the oestrogens is to administer the oestrogens transdermally so that it would by-pass the hepatic clearance.¹⁹

Conclusion

Climacteric period is important in a woman"s life. The increased risks of osteoporosis and cardiovascular diseases are two major public health problems with significant morbidity and mortality. Some women may also need to re-adjust psychologically in this period. Malignancy, which is not directly related to menopause but more age-related, is another risk for our concern. Therefore, preventive measures are essential. As a physician, it is important to see the individual"s need and manage accordingly.

If the main problem is vasomotor symptoms, counselling is vital to see if medications are necessary, e.g. short-term oestrogen therapy, clonidine or gabapentine. If the urogenital symptoms are serious, again short period of local oestrogen may help.

For the prevention of osteoporosis, Southern Medical Association had held an annual conference on postmenopausal osteoporosis. The summaries of the conference are as follows: Healthy diet is important throughout life. The public should be educated to have enough calcium and 25-hydroxyvitamin D levels either through diet or supplementation. The bisphosphonates (e.g. alendronate and risedronate) reduce the vertebral fracture risk by around 40 to 50% and nonvertebral fracture risk by around 30 to 40%, and hip fracture risk by around 40 to 60%. Salmon calcitonin nasal spray demonstrated significant reductions in vertebral fracture risk in pivotal studies. Teriparatide (PTH) significantly reduced vertebral and nonvertebral fracture risk. Drugs on the horizon include Ibandronate (a new bisphosphonate which can reduce vertebral fracture risk), zoledronic acid (an yearly injectable bisphosphonate to increase bone density) and strontium ranelate (which has been shown to reduce both vertebral and nonvertebral fracture risk).²⁰

The bisphosphonates (alendronate and risedronate) significantly reduce the risk of both vertebral and non-vertebral (e.g. hip) fractures. The once-weekly formulation is another advantage of these agents as this provides a convenient way of administration. The alendronate and SERM raloxifene protect against vertebral fracture after 1 year of treatment, and risedronate markedly reduces the rate of vertebral and nonvertebral fractures after 6 months of treatment. But they are contraindicated in patients with upper gastrointestinal diseases. Calcitonin also reduces the risk of vertebral, but not nonvertebral, fractures. Calcitonin is a good option in patients with back pain because of its analgesic effect. Raloxifene is especially useful in patients with dyslipidaemia, high risk of cardiovascular or cerebrovascular diseases, or a family history of breast cancer. Teriparatide is indicated in subjects with very low BMD and multiple vertebral fractures.^21,22

In addition to the use of drug, healthy lifestyle is to be adopted. For example, menopausal ladies should have a healthy diet (more fibres, less fat and less saturated fat), regular exercises (but with attention that the exercises should not be stressful or damage the brittle skeleton), and lead a less stressful life or have a less stressful career. Smoking reduces the effect of oestrogen on bone metabolism and this is mediated by an adverse influence on sex-steroid metabolism. Therefore, smoking should be stopped.²³

Other alternatives like phyto-oestrogens, androgens, omega 3 have not been proven scientifically to be beneficial or harmful. Until such data exists, physicians should be very careful when they counsel someone on the long-term and regular use of these drugs.²⁴ It is not advisable to use the expensive yet unproven therapies as the possible side-effects from long-term administration are still uncertain.

Studies have suggested that space flying may accelerate bone loss. With the future development of more space flying studies in this area would be interesting. Also these studies may lead to potential therapeutic interventions based on the molecular and cell biology researches (e.g. the manipulation of LRP5, Wnt and BMP2 pathways, or RANK-L/osteoprotegerin signaling pathway) to stipulate the bone turnover by regulating osteoclast formation and maturation.²⁵

Key messages

1. Alternatives like phyto-oestrogens and omega-3 do not have adequate and powerful RCT to document their efficacy in the healthcare of a menopausal lady.
2. The efficacy of biphosphonates to maintain bone density and prevent fractures has been proven by adequate clinical trials.
3. Parathyroid hormone (PTH) is the only drug available in the market that may increase (instead of maintain) the bone density in osteopenic or osteoporotic patients. But long term study is required especially with regard to its safety in prolonged administration.
4. For menopausal ladies, unless contraindication exists (e.g. breast cancer or thrombo-embolic phenomenon), raloxifene should be considered as it provides multiple advantages. Short term ERT/HRT may be used for vasomotor symptoms if clonidine or gabapentine does not provide relief. ERT may also be used for short period for urogenital symptoms.

---

---

References