Hormonal modulation：CLOMIPHENE

General description

Clomiphene is an antiestrogen thought to increase sperm parameters in males attempting to conceive. The objective of this review was to evaluate the efficacy and safety of Clomiphene citrate in the treatment of male patients with infertility. It is an oral agent used to treat infertility in women desiring pregnancy. Clomiphene has been linked to a low rate of transient serum aminotransferase elevations during therapy and to rare instances of clinically apparent liver injury, which can be severe and even fatal.A triphenyl ethylene stilbene derivative which is an estrogen agonist or antagonist depending on the target tissue.

CLOMIPHENE is a combination of trans and cis isomers, Clomiphene, that have estrogen receptor antagonistic and agonistic properties, respectively. This fact led to the development of Clomiphene citrate, a preparation of the transisomer only. Phase 2 studies have shown a significant increase in serum testosterone levels with Clomiphene while preserving or improving spermatogenesis. Similarfindings were reported with Clomiphene in a population of obese men. Clomiphene citrate has yet to receive FDA approval owing to concerns that Phase 3 studies were not adequately designed to show clinical benefit in the target population of men with secondary hypogonadism and oligospermia.

Application and pharmacology

CLOMIPHENE is used off-label for the treatment of hypogonadism, especially in men who wish to maintain fertility potential. CLOMIPHENE treatment increases serum testosterone levels as demonstrated in multiple studies and does not appear to adversely alter the T:E ratio. Results from studies on symptom relief from CLOMIPHENE are conflicting, but there does appear to be an overwhelming suggestion that it improves the symptoms of hypogonadism. Many studies have found it to be a largely safe and cost-effective drug with health benefits, such as improving bone density, in hypogonadal men. We believe that CLOMIPHENE is a safe and effective drug that should remain in the armament of urologists treating hypogonadal men.

Hormonal modulation：CLOMIPHENE exerts its effects centrally with a result of increased LH and FSH secretion and increased testicular testosterone production. Many studies have described significant increases in serum testosterone, LH, and FSH with CLOMIPHENE treatment. Studies have revealed comparable increases in serum testosterone levels in hypogonadal men treated with CLOMIPHENE compared with TRT. CLOMIPHENE has also been compared with aromatase inhibitors, such as anastrozole, and CLOMIPHENE has proven to be more effective in increasing testosterone levels.

Synthesis

Add diisobutyl aluminum hydride dropwise to the hexane solution of Diphenylacetylene, react at room temperature for hours and at ° C for hours, and cool to room temperature for standby. Tetratriphenyllin and 1-cation-diethylaminoethoxy] o-benzene were mixed, the above vinyl aluminoalkane solution was added and refluxed for hours to obtain a yield of Shun.[1]

The systhesis route of the intermediate of Clomifene

History

Clomiphene citrate (CLOMIPHENE) is a selective estrogen receptor modulator initially developed for treatment of female infertility in the 1960s. It inhibits the negative feedback of estrogen at the level of the hypothalamus and pituitary. This results in increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. In women, CLOMIPHENE is used for ovulation induction, whereas in men it stimulates the production of testosterone in Leydig cells. It has been used since the 1970s as an off-label treatment for hypogonadism, especially for men wanting to maintain fertility, because CLOMIPHENE avoids the pathway of impaired spermatogenesis caused by testosterone replacement therapy (TRT). We aim to review the literature on the use of CLOMIPHENE in the treatment of hypogonadism.[2]

Toxicity

CLOMIPHENE may result in an increase in estrogen production, altering the testosterone to estrogen (T:E) ratio and increasing estrogenic side effects, although there is limited data to support this. In a small retrospective study, Shabsigh et al showed a rise in the T:E ratio after low-dose CLOMIPHENE treatment. Ramasamy et showed no significant rise in serum estradiol in CLOMIPHENE-treated men when compared with testosterone replacement gels or placebo. In a small randomized trial, Helo el al16showed CLOMIPHENE increased T:E ratio in hypogonadal infertile men, although to a lesser degree than anastrazole. The significance of T:E ratio in hypogonadal men is unclear. Gupta et al18showed that T:E ratio was more predictive of low libido than total testosterone levels, but this was in cardiac patients, only 55% of whom were biochemically hypogonadal. Patients may still elect to take Clomiphene, though they should be counseled regarding side effects and given realistic expectations of the medication with pregnancy rates generally 10%to 20%.13–22Patients more likely to benefit from the treatment with Clomiphene may include those meeting the following criteria: men with a diagnosis of idiopathic infertility, sperm concentrations <20 million/mL but greater than 10 million/mL, normal FSH and LH levels, and normal or slightly below normal motility and morphology. Patients with a sperm concentration <5 million/mL should not be treated with Clomiphene, as it has not shown benefit in this population. [3]

Reference

1.Yu Xiong，One step synthesis of Clomiphene intermediate

2.Willets A. E., Corbo J. M. & Brown J. N., "Clomiphene for the Treatment of Male Infertility," Reproductive Sciences, Vol.20, No.7(2013), pp.739-744.

3.Wheeler K. M., Sharma D. & Kavoussi P. K. et al., "Clomiphene Citrate for the Treatment of Hypogonadism," Sexual Medicine Reviews, Vol.7, No.2(2019), pp.272-276.