Clomiphene

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Clomiphene

Clomiphene

Clomiphene also called clomiphene citrate is a man-made (synthetic) fertility medicine or selective estrogen receptor modulator (SERM) that causes your pituitary gland to release hormones needed to stimulate ovulation (the release of an egg from women’s ovary) to become pregnant. Clomiphene is used treat of anovulatory or oligo-ovulatory infertility in women with certain medical conditions such as polycystic ovary syndrome (PCOS) that prevent naturally occurring ovulation. Clomiphene works similarly to estrogen, a female hormone that causes eggs to develop in the ovaries and be released. In clinical trials, clomiphene resulted in pregnancies in approximately 30% of patients 1. Clomiphene was approved for use in the United States in 1967, and current indications are for treatment of ovulatory dysfunction in women desiring pregnancy 1.

Clomiphene is also sometimes used to treat hypogonadism (low testosterone) to induce spermatogenesis in men who are interested in fertility, menstrual abnormalities, fibrocystic breasts, and persistent breast milk production. Clomiphene citrate is also known to be abused by athletes such as bodybuilders and weightlifters for performance enhancement because it raises serum testosterone and gonadotropin levels 2, 3, 4.

Do not use clomiphene if you are already pregnant. You should not use clomiphene if you have liver disease, unexplained abnormal vaginal bleeding, an uncontrolled adrenal gland or thyroid disorder, an ovarian cyst (unrelated to polycystic ovary syndrome), or if you are pregnant.

Clomiphene is available in tablets of 50 mg generically and under the brand name Clomid to be taken by mouth. The recommended dose is 50 mg daily for 5 days, beginning on or about day 5 of your menstrual cycle. To help you remember to take clomiphene, take it around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take clomiphene exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Talk to your doctor about the possible risks of using clomiphene for your condition.

Some reported side effects from using clomiphene include headache, dizziness, anorexia, diarrhea, rash, worsening of psychiatric illnesses, gynecomastia (an increase in the amount of breast gland tissue in boys or men), testicular tumor, vasomotor flushing, gastrointestinal disturbance, and breast pain (mastalgia) 5, 6. Other common adverse reactions are nausea, vomiting, ovarian enlargement, blurred vision, sparkling blind spot (scintillating scotoma), abnormal uterine bleeding, pelvic pain, and hypertriglyceridemia. Some serious reactions to the use of clomiphene are multiple pregnancies, ovarian hyperstimulation syndrome (OHSS), thrombocytopenia, pancreatitis, risk of ovarian cancer after prolonged use, increased risk of malignant melanoma, severe visual disturbance, kidney and liver damage 7, 8, 9, 10.

Ovarian hyperstimulation syndrome (OHSS) is reported in women using clomiphene citrate therapy for ovulation induction. Ovarian hyperstimulation syndrome (OHSS) can progress rapidly (within 24 hours) and become a medical emergency 11.

Clomiphene warnings

Clomiphene citrate is a pregnancy category X drug; it is contraindicated to use clomiphene in pregnant women. Do not use clomiphene if you are already pregnant. There is some published evidence of possible teratogenicity (the ability to cause defects in a developing fetus), mainly neural tube defects and hypospadias; however, additional investigation is essential to permit the safer use of clomiphene 12.

You should not use clomiphene if you have liver disease, unexplained abnormal vaginal bleeding, an uncontrolled adrenal gland or thyroid disorder, an ovarian cyst (unrelated to polycystic ovary syndrome), or if you are pregnant.

Clomiphene citrate contraindications

The following are contraindications for the use of clomiphene citrate:

  • Hypersensitivity to clomiphene citrate or components of the formulation
  • Pregnancy
  • Breastfeeding
  • History of liver 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

Clomiphene special precautions

Before taking clomiphene:

  • tell your doctor and pharmacist if you are allergic to clomiphene or any other medications.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking.
  • tell your doctor if you have or have ever had liver disease, ovarian cysts (except those from polycystic ovary syndrome [PCOS]), uterine fibroids, abnormal vaginal bleeding, a pituitary tumor or other brain tumor, or thyroid or adrenal disease.
  • tell your doctor if you are pregnant or breast-feeding. If you become pregnant while taking clomiphene, call your doctor immediately.
  • you should know that clomiphene may cause blurred vision. Do not drive a car or operate machinery, especially in poor lighting, until you know how this medication affects you.
  • you should know that clomiphene increases the chance of multiple pregnancy (twins or more). Talk to your doctor about the risks of multiple pregnancy.

To make sure clomiphene is safe for you, tell your doctor if you have:

What special dietary instructions should I follow?

Unless your doctor tells you otherwise, continue your normal diet.

Clomiphene mechanism of action

Clomiphene citrate is a selective estrogen receptor modulator (SERM) 11. Clomiphene selectively binds to estrogen receptors in your brain at the hypothalamus, pituitary, ovary, endometrium, vagina and cervix, producing estrogenic and anti-estrogenic effects 11. The inhibition of estrogen effects by clomiphene leads to release of pituitary follicular stimulating hormone (FSH), which initiates growth and maturation of the ovarian follicle, follicular rupture and ovulation.

Clomiphene also acts as a partial estrogen agonist in the hypothalamus, resulting in a negative estrogenic feedback inhibition, therefore increasing gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) 13. Clomiphene increases the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), therefore increasing the production of serum levels of testosterone 14. Clomiphene is also used as an add-on to alleviate pituitary suppression 15.

Clomiphene citrate pharmacokinetics

  • (i) Absorption: In early radiolabeled clinical studies, research has shown that clomiphene citrate is readily absorbed orally.
  • (ii) Metabolism: Based on a single-dose healthy volunteer clinical study, it is evident that zuclomiphene has a longer half-life than enclomiphene and may remain longer than a month in these volunteers.
  • (iii) Elimination: About half of the orally administered dose of clomiphene is excreted in urine (8%) and feces (42%).

Clomiphene uses

Clomiphene citrate is an United States Food and Drug Administration (FDA)-approved selective estrogen receptor modulator (SERM) to treat anovulatory or oligo-ovulatory infertility in women to induce ovulation for women desiring to get pregnant 16. Using clomiphene to induce pregnancy in women with polycystic ovary syndrome (PCOS) can result in a 6-month live birth rate of 20% to 40% 17. Clomiphene can either be used alone or with an add-on, such as flying needling therapy (acupuncture) for ovulation failure in women with polycystic ovary syndrome (PCOS) 18.

Women most likely to benefit from clomiphene citrate are women 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. Patients indicated for clomiphene therapy must not have an ovarian cyst, vaginal bleeding, or liver disease 19, 20, 21, 22.

Clomiphene citrate is also often used off-label by men to treat both male infertility and secondary hypogonadism because it increases serum testosterone levels 23, 24.

Studies have found clomiphene citrate effective in treating and preventing short-lasting unilateral neuralgiform headache attacks (SUNCT), a trigeminal autonomic cephalalgias subform. Clomiphene has not been FDA-approved for the treatment of short-lasting unilateral neuralgiform headache attacks (SUNCT). However, a case study of a 65-year-old man who had frequent headaches for years and was refractory to treatment was finally diagnosed with short-lasting unilateral neuralgiform headache attacks (SUNCT) syndrome 25. He was initiated on 50 mg of clomiphene daily for 2 weeks 25. Four days after clomiphene citrate therapy initiation, the frequency of his headaches reduced, but the pain did not subside entirely. The dose was increased to 75 mg daily, and after day 5, the patient became pain-free. After 1.5 months on this dosage, the patient was doing well but experienced a slight recurrence of the attack. His physician increased his clomiphene dose to 100 mg/d, and he had no attacks for 3 months. At this point, the clomiphene was tapered off, and 4 months after discontinuing clomiphene, the patient continued to be pain-free 25.

  1. FDA-Approved Indications
    • Anovulatory or oligo-ovulatory infertility (ovulation induction)
    • Male infertility (spermatogenesis induction)
  2. Off-Label Uses
    • Secondary hypogonadism (hypogonadotropic hypogonadism) 26
    • Performance enhancement for healthy athletes 27
    • Primary short-lasting unilateral neuralgiform headache attacks (SUNCT)

Clomiphene dose

Clomiphene citrate is available as a 50 mg oral tablet.

Adult dosage for Ovulation Induction

Your doctor will perform medical tests to make sure you do not have conditions that would prevent you from safely using clomiphene. Clomiphene citrate dosage is 50 mg daily (1 tablet) for 5 days. Treatment should start on day 5 of your menstrual period if there is spontaneous or induced bleeding. Follow your doctor’s instructions. If you do not ovulate during the first cycle, clomiphene citrate dose can be increased to 100 mg per day (2 x 50 mg tablets taken as a single daily dose) for 5 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 (OHSS) 28. You will need to have a pelvic examination before each treatment cycle to exclude pregnancy, ovarian enlargement, or ovarian cyst formation. You must remain under the care of a doctor while you are using this medicine.

You will most likely ovulate within 5 to 10 days after you take clomiphene. To improve your chance of becoming pregnant, you should have sexual intercourse while you are ovulating. Follow your doctor’s instructions regarding timed intercourse.

Your doctor may have you use over-the-counter ovulation tests or check your temperature each morning and record your daily readings on a chart. This will help you determine when you can expect ovulation to occur.

If you ovulate during the first cycle but do not become pregnant, there is no advantage to increasing clomiphene citrate dose in subsequent cycles. If ovulation does not occur during the first treatment cycle, then clomiphene citrate dosage can be increased to 100 mg daily for 5 days. The second treatment cycle may commence as early as 30 days after the prior cycle, provided that the patient is negative for pregnancy. Recommendations do not include increasing the dosage or duration of therapy beyond 100 mg per day for 5 days.

Most women who will ovulate normally do so after the initial cycle of clomiphene therapy. If you do not ovulate after 3 cycles of clomiphene citrate therapy, further treatment with clomiphene citrate is not recommended. Your doctor may stop treatment and evaluate your infertility further. Treatment should be discontinued if the patient ovulates 3 times but does not get pregnant. 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 6 cycles of clomiphene therapy, thus avoiding severe side effects or toxicity due to the overuse of clomiphene citrate.

Adult dosage for Sperm production

Clomiphene citrate for sperm production (spermatogenesis) is 25 mg daily (half of a tablet) for 25 days and off for 5 days. Alternative administration is a 25 mg oral tablet every other day. Semen analysis to evaluate spermatozoa level and motility should occur regularly. The dose can be increased to 50 mg daily for 25 days and off for 5 days.

The biochemical response of clomiphene citrate may vary. Therefore, when treating men with hypogonadism or infertility, it is suggested to perform lab evaluations for testosterone levels and semen analysis at regular intervals. Assessing prostate-specific antigen (PSA) or hematocrit (the percentage by volume of red cells in your blood) levels is not necessary since they are not affected by using clomiphene citrate 29.

Treating males with infertility also requires an interprofessional healthcare team across various disciplines. Patient education is paramount to limit side effects due to the long-term use of clomiphene citrate. This is best accomplished by an interprofessional team effort between the patient and all healthcare professionals (ie, clinicians and pharmacists) involved in the patient’s treatment. This interprofessional approach will lead to the best patient outcomes 30, 31.

Adult dosage to suppress lactation and breastmilk

A double-blind study compared clomiphene in dosages of 50 mg daily for 10 days (n = 110), 100 mg daily for 5 days (n = 26) and placebo (n = 41) in their ability to suppress lactation and relieve pain and engorgement in nonnursing postpartum mothers. Both dosages of clomiphene were superior to placebo as reported by the women, but the 100 mg daily dosage was somewhat superior to the 50 mg daily dosage 32.

A study compared clomiphene 100 mg daily for 5 days (n = 60) to placebo (n = 30) in suppressing lactation and symptoms of breast engorgement 33. Starting clomiphene within 12 hours of delivery was more effective in all measures than starting it 12 hours or more after delivery as judged by a physician observer; both treatments were more effective than mechanical measures alone such as breast binding 33.

A randomized trial compared clomiphene 50 mg twice daily for 14 days (n = 15) to bromocriptine 2.5 mg twice daily for 14 days (n = 15), diethylstilbestrol 5 mg 3 times daily for 14 days (n = 15), testosterone propionate 75 mg intramuscularly once (n = 15), and placebo 3 times daily by mouth (n = 15) in their ability to reduce serum prolactin and lactation postpartum 34. After three days of treatment, serum prolactin was reduced to 65% of baseline by clomiphene compared to a drop to 35% in patients who received bromocriptine 34. Clomiphene was also less effective than bromocriptine in suppressing lactation and symptoms of breast engorgement 34.

A study compared clomiphene 100 mg daily for 7 days (n = 10) to placebo (n = 12) started on the first day postpartum 35. Clomiphene was no more effective than placebo in suppressing lactation or reducing serum prolactin concentrations 35.

Women in the first week postpartum who did not wish to breastfeed received either clomiphene 50 mg twice daily (n = 10) or placebo (n = 10) 36. Women who received clomiphene did not experience a rise in serum prolactin from baseline values during use of a breast pump; those given placebo had the normal post-stimulation rise in serum prolactin 36.

Eighty postpartum women were studied. Forty received clomiphene 50 mg twice daily for 5 days beginning the first day postpartum; 20 received clomiphene 50 mg twice daily for 5 days beginning the fourth day postpartum; and, 20 received placebo 37. All women receiving clomiphene experienced inhibition of lactation, and reductions in breast engorgement, discomfort and serum prolactin. Prolactin serum concentrations became statistically lower than baseline on day 3 for the women who were 1 day postpartum and on day 5 for those who were 4 days postpartum at the outset. Placebo did not suppress lactation nor suppress serum prolactin 37.

Adult dosage for short-lasting unilateral neuralgiform headache attacks (SUNCT)

Chronic Short-Lasting Unilateral Neuralgiform Headache Attacks (SUNCT) (off-label use if SUNCT is refractory to other recommended medications): The initial recommended dose is 50 mg orally daily. The maximum daily dose is 100 mg orally 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.

Dosage adjustment

  • (i) Liver Impairment: No dose adjustment information is available for patients with hepatic impairment. However, the recommendation is to use clomiphene in patients with normal liver functions.
  • (ii) Kidney Impairment: No dose adjustment information is available for patients with renal impairment.
  • (iii) Breastfeeding: Clomiphene appeared in low amounts in milk in one woman 38, 39. Many drugs are excreted in human milk, so caution should be taken when clomiphene is administered to breastfeeding women. Several studies found that clomiphene suppresses lactation in women who did not want to breastfeed. Clomiphene appears to act by lowering serum prolactin, especially the post-stimulation surge in serum prolactin. It is likely that clomiphene would interfere with lactation in a nursing mother 39.
  • (iv) Pregnancy: Clomiphene citrate is a pregnancy category X drug; it is contraindicated to use clomiphene in pregnant women as this treatment has no additional benefits in this patient population. Human data on clomiphene do not suggest any increased risk related to congenital abnormalities. However, animal reproductive toxicology studies observed increased structural malformations and embryo-fetal loss 39.

Clomiphene monitoring

Your doctor should monitor your fasting lipid panel (a complete cholesterol test that measures the amount of cholesterol and triglycerides in your blood) at baseline and then periodically if you are at risk for hypertriglyceridemia. Conduct a pregnancy test and perform a pelvic exam before initiating clomiphene citrate therapy and before each treatment cycle. Patients with any visual symptoms should discontinue treatment with clomiphene and have a complete eye evaluation conducted promptly.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, call your doctor for additional directions. Do not take a double dose to make up for a missed one.

Clomiphene side effects

Clomiphene may cause side effects.

Common clomiphene side effects may include:

  • flushing (warmth, redness, or tingly feeling)
  • breast pain or tenderness
  • headache
  • breakthrough bleeding or spotting.

Tell your doctor if any of these symptoms are severe or do not go away:

  • flushing (feeling of warmth)
  • upset stomach
  • vomiting
  • breast discomfort
  • headache
  • abnormal vaginal bleeding

Some side effects can be serious. The following symptoms are uncommon, but if you experience any of them, see your doctor immediately:

  • blurred vision
  • increased sensitivity of your eyes to light
  • visual spots or flashes
  • seeing flashes of light or “floaters” in your vision
  • double vision
  • stomach or lower stomach pain
  • pelvic pain or pressure, enlargement in your pelvic area
  • stomach swelling
  • weight gain
  • shortness of breath
  • heavy vaginal bleeding.

Long-term use of clomiphene may increase the risk of ovarian cancer. Clomiphene should not be used for more than about six cycles. Talk to your doctor about the risks of taking clomiphene.

Clomiphene may cause other side effects. See your doctor if you have any unusual problems while taking clomiphene.

Symptoms of clomiphene overdose may include:

  • upset stomach
  • vomiting
  • hot flashes
  • blurred vision
  • visual spots or flashes
  • blind spots
  • stomach swelling
  • stomach or lower stomach pain.

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 (blurring or spots in your vision), ovarian enlargement, and pelvic and abdominal pain. Clomiphene is also toxic to the kidneys after prolonged use.

There is no known antidote for the overdose of clomiphene citrate; however, gastric lavage and other supportive procedures are necessary.

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