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WRITE UPS - MENOPAUSE - Selective Estrogen Receptor Modulators

INTRODUCTION:

The discovery of pharmacologic agents that can be estrogenic in some tissues and antiestrogenic in others has led to intense activity in better understanding of the mechanism by which molecular structure interacts with cellular receptors to selectively affect DNA transcription in different organs. This concept has given a major boost in research work for menopausal management with the hope of developing and agent that could confer all the benefits of estrogen without any of its risks.

 DEFINITION:

SERMs(Selective Estrogen Receptor Modulators) are structurally diverse compounds that bind the estrogen receptors (ER) and elicit agonist or antagonist responses depending on the target tissues and hormonal milieu1.
They as also often referred to as “Tissue Specific Estrogens” or “Designer Estrogens”. In addition to tissue specific variance in estrogen agonist and antagonist action, the agonist- antagonist profile of a SERMs may vary depending on a women‘s endogenous estrogen milieu, therefore findings noted in post menopausal women should not necessarily be generalized to premenopausal women.

 HISTORY:

SERMs have been available for clinical use since the late 1960s. By the late 1980s, several SERMs had become available that influenced clinical practice. Multi-organ effects of these compounds include variable clinical efficacy for treatment of menopausal symptoms involving the central nervous system, variable effects on the genitourinary tract, and, in general, positive effects on serum lipid levels2. Recent advance in molecular biology and identification of atleast two (ERα and ERβ receptors) have resulted in development SERMs.

The concept of SERM evolved in the pursuit of research for “Anti Estrogens” like clomiphene & Tamoxifen etc. Tamoxifen was tried initially and discarded for its use in menopausal management due to high incidence of endometrial proliferation and endometrial malignancy.

 THE GROUP:

Although the term selective estrogen receptor modulator (SERM) is loosely defined and the underlying mechanism of action remaining unclear, this class of drugs may include:

A) A 19- Nor testosterone derivative: Tibolone
B) Non-steroidal Benzothiophene compounds like Reloxifene and its analogues
C) Newer triphenylethylene derivatives such as Droloxifene, Toremifene, Idoxifene Levomeloxifiene, Ormeloxifene.

 POSSIBLE MECHANISMS OF ACTION:

 A) Differences in binding affinities to the estrogen receptor.
B) Differential changes in estrogen receptor structure after ligand binding.
C)   Affects transcriptional regulation by the estrogen receptors (ERα and ERβ) but show different effects in different tissues3.

 RALOXIFENE:

Raloxifene is the most extensively studied molecule in SERMs. As shown in table I, it shows estrogen agonist effects on the skeleton and lipids resulting in significant reduction in fracture rates and favourable lipid profile. Furthermore, this selective estrogen receptor modulator may enable dissociation of estrogen risks and benefits 4.

On the other hand it exerts estrogen antagonistic effects on breast and uterine tissues resulting in protective effects on their malignancies. Raloxifene did not have any detectable effect on the parathyroid hormone set-point. An effect on non-suppressible PTH secretion cannot be excluded as of today3. Raloxifene does not relieve menopausal symptoms such as hot flushes. Possible effects on cardiovascular system and CNS have not been clearly identified.

Raloxifene is used in the does of 60-120mg/day with remarkable safety. The side effects are mild and include hot flushes, mild leg cramps and occasionally vaginal discharge.

Most serous risk of Raloxifene is three fold increase in venous thremboembolism.

 CONCLUSION:

Although the role of SERMs in the treatment of breast cancer and that of Reloxifene in prevention of osteoporosis is well established, their proposed use as an alternative to HRT in healthy postmenopausal women is unsubstantiated. The risk-benefit ratio of the emerging SERMs needs to be better defined & evaluated.

The clinical use of SERMs has yet to demonstrate the beneficial effects shown with HRT on all cause mortality, colon cancer, CNS (i.e. risk of Alzheimer’s disease, improved cognition).

As many menopausal women seek medical help due to symptoms like hot flushes exacerbation of these symptoms due to Raloxifene & other SERMs makes them unpopular too.

In spite of this hot debate it is very certain that SERMs have opened up a new world of tissue specific agents that will go a long way improving the find of agents that would have precisely executed effects and in turn make life better.

 REFERENCES: 

1. Boker V. L. Jaffe R. B. Clinical Uses of anti estrogens: Obst.& Gynec. Survey: 1996;51;45-59.

2. Whitaker MD: Selective estrogen receptor modulators: from bench to bedside and back: Endocr Pract 2001 Mar-Apr; 7(2): 113-9

3. Oleksik A, Duong T, Popp-Snijders C, Pliester N, Asma G, Lips P: Effects of the selective estrogen receptor modulator-raloxifene-on calcium and PTH secretory dynamics in women with osteoporosis: Clin Endocrinol (Oxf) 2001 May; 54(5):575-82

4. Wenger N K: Hormonal and Non-hormonal Therapies for the Postmenopausal Woman: What is the Evidence for Cardio protection? Am J Geriatr Cardiol 2000 Jul; 9(4): 204-209

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