Raloxifene or Clomiphene: what is the difference

Raloxifene and clomiphene formally belong to the same class — selective estrogen receptor modulators. But whereas clomiphene was created to "trick" the hypothalamus and stimulate ovulation, raloxifene was created to protect the bones of postmenopausal women without stimulating the uterus and the breast. The editorial team explains how these molecules differ in essence.

Two generations of SERMs

Clomiphene belongs to the first generation of estrogen receptor modulators. It was registered in the 1960s for the treatment of anovulatory infertility, and since then has remained one of the best-known agents in reproductive medicine. Clomiphene is a mixture of two isomers — enclomiphene and zuclomiphene — with different properties.

Raloxifene is a representative of the second generation. It was developed already with the understanding that tamoxifen stimulates the endometrium and increases the risk of uterine cancer. The goal was to obtain a compound that would act like estrogen on the bones and lipids but would not stimulate breast and uterine tissue.

Raloxifene is registered for the treatment and prevention of osteoporosis in postmenopausal women, and in the USA also for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis or high risk. The official daily dose stated in the label is 60 mg.

Thus, these two drugs effectively solve opposite tasks. Clomiphene enhances the hormonal activity of the axis by blocking the central feedback, while raloxifene is intended for long-term use to affect peripheral tissues.

Chemical structure and pharmacokinetics

Clomiphene, like tamoxifen, is a derivative of triphenylethylene. Raloxifene has a different basis — benzothiophene. This structural difference determines how the molecule sits in the pocket of the estrogen receptor and which coregulator proteins attach to the complex, which ultimately shapes the tissue profile of action.

The oral bioavailability of raloxifene is very low — about 2%, according to the official label, since the drug binds intensively to glucuronic acid already in the intestine and liver. However, it undergoes enterohepatic circulation, which prolongs its presence in the body; the half-life is about a day.

Clomiphene is well absorbed. Its isomers behave differently: enclomiphene is eliminated relatively quickly, while zuclomiphene has a very long half-life and can be detected in the blood weeks after intake. That is why, with repeated courses of clomiphene, the estrogenic isomer gradually accumulates.

Practical conclusion: raloxifene is designed for daily long-term use with a steady concentration, while clomiphene is designed for short cycles tied to a woman's menstrual cycle.

Tissue profiles: bone, uterus, brain

In bone tissue raloxifene acts as an estrogen-like agonist: it suppresses bone resorption and maintains mineral density. In the MORE study (Ettinger et al., 1999) in women with osteoporosis, raloxifene reduced the risk of new vertebral (spinal) fractures, although an effect on non-vertebral fractures was not demonstrated.

In the breast raloxifene is an antagonist. In the STAR study (Vogel et al., 2006) it showed effectiveness in reducing the risk of invasive breast cancer, comparable to tamoxifen, with fewer cases of endometrial cancer and thromboembolism. In the endometrium raloxifene, unlike tamoxifen, has no noticeable stimulating action.

Clomiphene has been studied mainly from the standpoint of its action on the hypothalamus and ovaries. Its central antiestrogenic action is the basis of ovulation induction. At the same time, on the endometrium and cervical mucus clomiphene can act antiestrogenically, which sometimes explains the discrepancy between the rate of ovulation and the rate of pregnancy.

What is important: in the hypothalamus raloxifene as an antagonist acts much more weakly than clomiphene. So raloxifene is not used to stimulate ovulation, and clomiphene is not used to prevent osteoporosis.

Effect on the hormonal axis

In women clomiphene blocks the estrogen receptors of the hypothalamus, as a result of which the secretion of GnRH, LH and FSH rises, and this stimulates the maturation of follicles. In men the same mechanism raises LH and testosterone, so clomiphene is used off-label for secondary hypogonadism (Huijben et al., 2022).

In postmenopausal women raloxifene does not substantially affect gonadotropins, since the ovaries no longer function. In men raloxifene has been studied in small studies; some increase in LH and testosterone has been reported, but the effect is much more modest and less studied than for clomiphene.

In clinical practice raloxifene in men is most often discussed in the context of gynecomastia. A study by Lawrence and colleagues (2004) in adolescents with pubertal gynecomastia reported a reduction in tissue with raloxifene and tamoxifen, although it was a small retrospective observation.

So, in an endocrinological sense, clomiphene is an "axis stimulator", and raloxifene is a "peripheral modulator". Their therapeutic niches practically do not overlap.

Risks and adverse effects

Common to both drugs is the class-specific risk of venous thromboembolism. For raloxifene it is described in detail: in the RUTH study (Barrett-Connor et al., 2006) raloxifene did not affect the incidence of coronary events but increased the risk of venous thromboembolism and fatal stroke. The official label contains a corresponding warning.

Other common effects of raloxifene are hot flashes and cramps in the calf muscles. The drug is not prescribed to premenopausal women or during pregnancy.

Clomiphene is characterized by hot flashes, abdominal discomfort, ovarian enlargement, multiple pregnancy and, rarely, ovarian hyperstimulation syndrome. Vision disturbances (blurring, flickering) are grounds to stop taking it; the label explicitly requires an ophthalmological examination in such a case.

• Raloxifene:thrombosis, hot flashes, leg cramps, the risk of fatal stroke in women with high cardiovascular risk.
• Clomiphene:ovarian hyperstimulation, multiple pregnancy, vision disturbances, mood swings.
• Both:prohibited by WADA (section S4) for athletes.

Editorial conclusions

Raloxifene and clomiphene are estrogen receptor modulators of different generations with a different chemical basis and opposite clinical tasks. Raloxifene protects bones and reduces the risk of breast cancer in postmenopausal women without stimulating the endometrium. Clomiphene stimulates gonadotropins and is used for ovulation induction.

Differences in bioavailability and duration of presence in the body determine their regimen of use: long-term daily intake for raloxifene and short cycles for clomiphene.

Both drugs carry a risk of thromboembolism and are prohibited in sport, so their choice and use must be an exclusively medical decision.

We also recommend reading our materials on whom doctors prescribe raloxifene or clomiphene to, on the comparison of tamoxifen with enclomiphene, and on osteoporosis in athletes.

References

1. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282(7):637–645.
2. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295(23):2727–2741.
3. Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355(2):125–137.
4. Lawrence SE, Faught KA, Vethamuthu J, Lawson ML. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia. J Pediatr. 2004;145(1):71–76.
5. Huijben M, Lock MTWT, de Kemp VF, et al. Clomiphene citrate for men with hypogonadism: a systematic review and meta-analysis. Andrology. 2022;10(3):451–469.
6. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551–566.
7. World Anti-Doping Agency. Prohibited List. Montreal: WADA (чинна редакція).