Clomiphene

Article Author:
Marilyn Mbi Feh
Article Editor:
Roopma Wadhwa
Updated:
7/2/2020 10:33:56 AM
PubMed Link:
Clomiphene

Indications

Clomiphene, also called clomiphene citrate, a selective estrogen receptor modulator (SERM), is an FDA-approved medication indicated for the treatment of anovulatory or oligo-ovulatory infertility to induce ovulation for patients desiring to conceive.[1] According to studies, the use of clomiphene to induce pregnancy resulted in a 6-month live-birth rate of 20% to 40%.[2] It can either be used alone or with an adjuvant, such as the flying needling therapy (acupuncture).[3] The patients likely to benefit from clomiphene citrate, are patients diagnosed with polycystic ovarian syndrome (PCOS) and other causes of infertility such as post-oral-contraceptive amenorrhea, amenorrhea-galactorrhea syndrome, psychogenic amenorrhea as well as some cases of secondary amenorrhea. Further, patients indicated for clomiphene therapy must not have an ovarian cyst, vaginal bleeding, or hepatic impairment.[4][5][6][7]

It is also often used in an off-label setting by men to treat both male infertility and secondary hypogonadism because of its ability to increase serum testosterone levels.[8][9][10][11][10][12][13][14][13][15][16]

Clomiphene citrate is also known to be abused by healthy athletes for performance enhancement purposes because it raises serum testosterone and gonadotropin levels.[17]

Studies have found clomiphene citrate to be effective in treating and preventing short-lasting unilateral neuralgiform headache attacks (SUNCT), a subform of trigeminal autonomic cephalalgias (TACs). It has not been FDA approved for the treatment of SUNCT. However, a case study of a 65-year-old patient who suffered frequent headaches for years and was refractory to treatment was finally diagnosed with SUNCT syndrome. The patient’s physician started him on 50 mg of clomiphene per day for two weeks. Four days after initiation of therapy, his frequency of headaches reduced, but the pain did not subside entirely. The dose was increased to 75 mg per day, and after day 5, the patient became pain-free. After 1.5 months of being on that dose and doing well, the patient experienced a slight recurrence of the attack. His physician increased his clomiphene dose to 100 mg per day, and he was void of attacks for three months, at which point, the clomiphene was tapered off, and four months after being free from clomiphene, the patient continued to be pain-free.[18]

FDA -Labeled Indication

  • Anovulatory or oligo-ovulatory infertility (Ovulation induction)
  • Male infertility (Spermatogenesis induction)

Non-FDA- labeled indication

  • Secondary hypogonadism
  • Performance enhancement for healthy athletes
  • Primary short-lasting unilateral neuralgiform headache attacks (SUNCT)

Mechanism of Action

Clomiphene is a selective estrogen receptor modulator (SERM). It selectively binds to estrogen receptors in the hypothalamus, ovary, endometrium, cervix and produces estrogenic and anti-estrogenic effects. It also acts as a partial estrogen agonist in the hypothalamus resulting in an estrogenic negative feedback inhibition, thus increasing gonadotropins.[19] It increases the secretion of luteinizing hormone as well as follicle-stimulating hormone, thus increasing the production of serum levels of testosterone.[11] It is also used as an adjuvant to alleviate pituitary suppression.[20]

Administration

Clomiphene citrate is available as a 50 mg oral tablet.

  • Ovulation Induction: 50 mg daily (1 tablet) for five days. Treatment should start on day 5 of the menstrual cycle if there is spontaneous or induced bleeding. If the patient does not ovulate during the first cycle, the dose can be increased to 100 mg per day (two 50 mg tablets taken as a single daily dose) for five days during the second cycle. Treatment is repeatable for up to 6 cycles. A low dosage or treatment duration is explicitly recommended for patients with PCOS to prevent ovarian hyperstimulation syndrome.[21]

Patients must be evaluated to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle.

Spermatogenesis induction: The regimen is 25 mg daily (half of a tablet) for 25 days, off for five days. Alternative administration is a 25 mg oral tablet every other day. Semen analysis to evaluate spermatozoa level and motility should take place at regular intervals. The dose can be increased to 50 mg daily for 25 days, off for five days.

Chronic short-lasting unilateral neuralgiform headache attacks (SUNCT) (off label use if SUNCT refractory to other recommended medications): Initial recommended dosing is 50mg orally daily. The maximum daily dose is 100mg orally daily until the patient becomes pain-free. Continue for a couple of months until the patient is out of cycle, at which point, clomiphene citrate should be tapered off.

Adverse Effects

Some reported adverse effects from the use of clomiphene are headache, dizziness, exacerbation of psychiatric illnesses, gynecomastia, testicular tumor, vasomotor flushing, gastrointestinal disturbance, and mastalgia.[11][22]

Other common adverse reactions are nausea, vomiting, ovarian enlargement, blurred vision, scintillating scotoma, abnormal uterine bleeding, pelvic pain, and hypertriglyceridemia.

Some serious reactions to the use of clomiphene are ovarian hyperstimulation, multiple pregnancies, thrombocytopenia, pancreatitis, risk of ovarian cancer after prolonged use, increased risk of malignant melanoma, severe visual disturbance and hepatic damage.[23][24][25][26]

Contraindications

 The following are contraindications for the use of clomiphene citrate.

  • Hypersensitivity to clomiphene citrate or components of the formulation
  • Pregnancy
  • Breastfeeding
  • History of hepatic impairment
  • Hepatic disease
  • Abnormal uterine bleeding
  • Uncontrolled adrenal dysfunction
  • Non-PCOS related ovarian cyst
  • Organic intracranial lesions
  • Uncontrolled thyroid disease
  • Pituitary tumor
  • Risk of hypertriglyceridemia
  • Endometrial cancer

Monitoring

The clinician should monitor fasting lipid panel at baseline then periodically if the patient is at risk for hypertriglyceridemia.

Conduct a pregnancy test and do a pelvic exam before initiating clomiphene citrate therapy and before each treatment cycle.

Toxicity

There are no reported toxic effects after the acute use of clomiphene citrate.

The signs and symptoms of clomiphene citrate therapy overdose include nausea, vomiting, visual disturbance, vasomotor flushes, scotoma, ovarian enlargement, pelvic and abdominal pain. It is also nephrotoxic after prolonged use.

There is no known antidote for the overdose of clomiphene citrate; however, gastric lavage and other supportive procedures are necessary. There is some published evidence of possible teratogenicity, mainly neural tube defect, and hypospadias; however, additional investigation is essential to permit safer use of clomiphene.[27]

Enhancing Healthcare Team Outcomes

Clomiphene citrate is commonly indicated for the treatment of patients diagnosed with anovulatory or oligo-ovulatory infertility to induce ovulation for patients wishing to conceive. It is also indicated for the treatment of male infertility to induce spermatogenesis. Treating patients with infertility requires an interprofessional team of healthcare professionals across various disciplines.[28][29] Procedures such as examining the patient, planning the treatment course and explanation of results are conducted by the clinician, while the explanation of methods and schedule as well as consultation of method and schedule, infertility counseling are performed by a team approach involving physicians experienced in managing endocrine and gynecologic disorders, embryologists, nurses, infertility counselors, and medical clerks.

Before initiating clomiphene citrate therapy, the physician must properly evaluate the patient to ensure that the patient meets the indications for clomiphene therapy, and the contraindications are not present. To achieve the goal of treatment, the physician must ensure that there are no inhibitors to the goal. If inhibitors exist, they require attention before initiating clomiphene citrate therapy.  The physician should outline the treatment plan with the patient in advance, and the patient should receive education on the objectives of therapy, balanced with potential risk. The importance of timed coitus to coincide with the expected ovulation period must be stressed to the patient since ovulation often occurs from 5 to 10 days after a cycle of clomiphene therapy. Advising the patient to use the ovulation test kit from 5 to 10 days after the treatment cycle to determine the ovulation day is a team effort.

If the patient ovulates during the first cycle but did not get pregnant, there is no advantage to increasing the dose in subsequent cycles. If ovulation does not occur during the first cycle of treatment, then the dosage can be increased to 100 mg per day for five days. The second treatment cycle may commence as early as 30 days after the prior cycle, provided that the patient is negative for pregnancy. It is not recommended to increase the dosage or duration of therapy beyond 100 mg per day for five days.

Most patients who will ovulate normally do so after the initial cycle of clomiphene therapy. If the patient does not ovulate after three cycles of clomiphene citrate therapy, further treatment with clomiphene citrate is not recommended. The patient will need further reevaluation. If the patient ovulates three times but does not get pregnant, treatment should discontinue. If the patient fails to menstruate after an ovulatory response, then reevaluate the patient. It is not recommended for the patient to have more than six cycles of clomiphene therapy, thus avoiding severe side effects or toxicity due to the overuse of clomiphene citrate.

The biochemical response of clomiphene citrate may vary. Therefore, when treating men with hypogonadism or infertility, it is suggested to do lab evaluations for testosterone levels and semen analysis at regular intervals. It is not necessary to assess PSA or HCT levels since they are not affected by the use of clomiphene citrate.[30] Treating males with infertility also requires an interprofessional healthcare team across various disciplines. Patient education is paramount to limit side effects due to long term use of clomiphene citrate, and this is best accomplished by a team effort between the patient and all healthcare professionals involved in the patient's treatment.

Recommendations for increasing successful outcomes in infertility therapy

  • Before initiating infertility treatment with clomiphene, first assess the underlying cause of the patient's anovulation and recommend lifestyle modifications or appropriately treat the causal medical condition.[1]
  • Patients and their physicians must monitor ovulatory response since it allows for a suitably timed intercourse or intrauterine insemination, respectively; this will assist in guiding any alternative therapies in case ovulation doesn't take place.[1]
  • Patients with hypothalamic hypogonadism may require exogenous gonadotropins as an alternative to oral agents.[1]
  • A patient that fails to conceive after being prescribed clomiphene therapy can be prescribed menotropin and a dose of human chorionic gonadotropin. The menotropin will stimulate the ovarian follicles, while the human chorionic gonadotropin will cause luteinizing hormone to surge.
  • In women with infertility due only to polycystic ovarian syndrome (PCOS) and are resistant to clomiphene (especially obese women), add metformin (an insulin sensitization agent) to the clomiphene regiment or prescribe gonadotropin as second-line pharmacologic therapy for ovulation induction.[4][5]
  • Combining metformin with clomiphene, in obese women, may increase pregnancy rates compared to clomiphene alone.[5][6]
  • Letrozole was found to induce ovulation at a similar rate as gonadotropin in clomiphene resistant PCOS patients, but with reduced risk compared with gonadotropin.[31]
  • Recent studies have shown letrozole, an aromatase inhibitor, to be the most effective oral agent than clomiphene or the combination of clomiphene and metformin to induce ovulation in patients with polycystic ovarian syndrome.[32][33][34][35]
  • Combining letrozole and clomiphene is associated with higher rates of ovulation compared with letrozole alone in patients with infertility and PCOS.[7]
  • Another second-line therapy is to perform laparoscopic ovarian surgery to induce ovulation in anovulatory women that have PCOS and no other fertility factors and be resistant to clomiphene.[4]

References

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