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. According to studies, the use of clomiphene to induce pregnancy resulted in a 6-month live-birth rate of 20% to 40%. It can either be used alone or with an adjuvant, such as the flying needling therapy (acupuncture). 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.
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.
Clomiphene citrate is also known to be abused by healthy athletes for performance enhancement purposes because it raises serum testosterone and gonadotropin levels.
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.
FDA -Labeled Indication
Non-FDA- labeled indication
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. It increases the secretion of luteinizing hormone as well as follicle-stimulating hormone, thus increasing the production of serum levels of testosterone. It is also used as an adjuvant to alleviate pituitary suppression.
Clomiphene citrate is available as a 50 mg oral tablet.
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.
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.
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.
The following are contraindications for the use of clomiphene citrate.
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.
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.
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. 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. 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
|||Von Hofe J,Bates GW, Ovulation induction. Obstetrics and gynecology clinics of North America. 2015 Mar; [PubMed PMID: 25681838]|
|||ACOG Practice Bulletin No. 194: Polycystic Ovary Syndrome. Obstetrics and gynecology. 2018 Jun; [PubMed PMID: 29794677]|
|||Ma H,Quan X,Chen X,Dong Y, [Flying needling therapy combined with clomiphene for ovulation failure in polycystic ovary syndrome:a randomized controlled trial]. Zhongguo zhen jiu = Chinese acupuncture [PubMed PMID: 29231300]|
|||Costello MF,Garad RM,Hart R,Homer H,Johnson L,Jordan C,Mocanu E,Qiao J,Rombauts L,Teede HJ,Vanky E,Venetis CA,Ledger WL, A Review of Second- and Third-line Infertility Treatments and Supporting Evidence in Women with Polycystic Ovary Syndrome. Medical sciences (Basel, Switzerland). 2019 Jun 26; [PubMed PMID: 31247909]|
|||Creanga AA,Bradley HM,McCormick C,Witkop CT, Use of metformin in polycystic ovary syndrome: a meta-analysis. Obstetrics and gynecology. 2008 Apr; [PubMed PMID: 18378757]|
|||Myers ER,Silva SG,Hafley G,Kunselman AR,Nestler JE,Legro RS, Estimating live birth rates after ovulation induction in polycystic ovary syndrome: sample size calculations for the pregnancy in polycystic ovary syndrome trial. Contemporary clinical trials. 2005 Jun; [PubMed PMID: 15911461]|
|||Mejia RB,Summers KM,Kresowik JD,Van Voorhis BJ, A randomized controlled trial of combination letrozole and clomiphene citrate or letrozole alone for ovulation induction in women with polycystic ovary syndrome. Fertility and sterility. 2019 Mar; [PubMed PMID: 30683591]|
|||Guay AT,Jacobson J,Perez JB,Hodge MB,Velasquez E, Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit? International journal of impotence research. 2003 Jun; [PubMed PMID: 12904801]|
|||Katz DJ,Nabulsi O,Tal R,Mulhall JP, Outcomes of clomiphene citrate treatment in young hypogonadal men. BJU international. 2012 Aug; [PubMed PMID: 22044663]|
|||Taylor F,Levine L, Clomiphene citrate and testosterone gel replacement therapy for male hypogonadism: efficacy and treatment cost. The journal of sexual medicine. 2010 Jan; [PubMed PMID: 19694928]|
|||Wheeler KM,Sharma D,Kavoussi PK,Smith RP,Costabile R, Clomiphene Citrate for the Treatment of Hypogonadism. Sexual medicine reviews. 2019 Apr; [PubMed PMID: 30522888]|
|||Pelusi C,Giagulli VA,Baccini M,Fanelli F,Mezzullo M,Fazzini A,Bianchi N,Carbone MD,De Pergola G,Mastroroberto M,Morselli Labate AM,Pasquali R, Clomiphene citrate effect in obese men with low serum testosterone treated with metformin due to dysmetabolic disorders: A randomized, double-blind, placebo-controlled study. PloS one. 2017; [PubMed PMID: 28886024]|
|||Habous M,Giona S,Tealab A,Aziz M,Williamson B,Nassar M,Abdelrahman Z,Remeah A,Abdelkader M,Binsaleh S,Muir G, Clomiphene citrate and human chorionic gonadotropin are both effective in restoring testosterone in hypogonadism: a short-course randomized study. BJU international. 2018 Nov; [PubMed PMID: 29772111]|
|||Moskovic DJ,Katz DJ,Akhavan A,Park K,Mulhall JP, Clomiphene citrate is safe and effective for long-term management of hypogonadism. BJU international. 2012 Nov; [PubMed PMID: 22458540]|
|||Patel DP,Brant WO,Myers JB,Presson AP,Johnstone EB,Dorais JA,Aston KI,Carrell DT,Hotaling JM, The safety and efficacy of clomiphene citrate in hypoandrogenic and subfertile men. International journal of impotence research. 2015 Nov-Dec; [PubMed PMID: 26289907]|
|||Roth LW,Ryan AR,Meacham RB, Clomiphene citrate in the management of male infertility. Seminars in reproductive medicine. 2013 Jul; [PubMed PMID: 23775379]|
|||Miller GD,Moore C,Nair V,Hill B,Willick SE,Rogol AD,Eichner D, Hypothalamic-Pituitary-Testicular Axis Effects and Urinary Detection Following Clomiphene Administration in Males. The Journal of clinical endocrinology and metabolism. 2019 Mar 1; [PubMed PMID: 30295816]|
|||Rozen TD, Complete alleviation of treatment refractory primary SUNCT syndrome with clomiphene citrate (a medicinal deep brain hypothalamic modulator). Cephalalgia : an international journal of headache. 2014 Oct; [PubMed PMID: 24662321]|
|||Adashi EY, Clomiphene citrate: mechanism(s) and site(s) of action--a hypothesis revisited. Fertility and sterility. 1984 Sep; [PubMed PMID: 6432584]|
|||Liu Y,Chen Q,Yu S,Wang Y,He W,Chang HY,Wang B,Gao H,Long H,Wang L,Lyu Q,Ai A,Kuang Y, Progestin-primed ovarian stimulation with or without clomiphene citrate supplementation in normal ovulatory women undergoing in vitro fertilization/intracytoplasmic sperm injection: A prospective randomized controlled trial. Clinical endocrinology. 2018 Mar; [PubMed PMID: 29247457]|
|||Davidson R,Motan T,Korownyk C, Clomiphene for anovulatory infertility. Canadian family physician Medecin de famille canadien. 2016 Jun; [PubMed PMID: 27303007]|
|||Jones T,Ho JR,Gualtieri M,Bruno-Gaston J,Chung K,Paulson RJ,Bendikson KA, Clomiphene Stair-Step Protocol for Women With Polycystic Ovary Syndrome. Obstetrics and gynecology. 2018 Jan; [PubMed PMID: 29215516]|
|||Berk-Krauss J,Bieber AK,Criscito MC,Grant-Kels JM,Driscoll MS,Keltz M,Pomeranz MK,Martires KJ,Liebman TN,Stein JA, Melanoma risk after in vitro fertilization: A review of the literature. Journal of the American Academy of Dermatology. 2018 Dec; [PubMed PMID: 30055204]|
|||Farzinvash Z, A young woman with sudden visual field shimmering: A case report. Indian journal of ophthalmology. 2018 Oct; [PubMed PMID: 30249855]|
|||Vervaet BA,Nast CC,Jayasumana C,Schreurs G,Roels F,Herath C,Kojc N,Samaee V,Rodrigo S,Gowrishankar S,Mousson C,Dassanayake R,Orantes CM,Vuiblet V,Rigothier C,D'Haese PC,De Broe ME, Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy. Kidney international. 2020 Feb; [PubMed PMID: 31892415]|
|||Del Pup L,Peccatori FA,Levi-Setti PE,Codacci-Pisanelli G,Patrizio P, Risk of cancer after assisted reproduction: a review of the available evidences and guidance to fertility counselors. European review for medical and pharmacological sciences. 2018 Nov; [PubMed PMID: 30536354]|
|||Scaparrotta A,Chiarelli F,Verrotti A, Potential Teratogenic Effects of Clomiphene Citrate. Drug safety. 2017 Sep; [PubMed PMID: 28547654]|
|||Yano K,Ohashi K, Interprofessional team approach to infertility treatment in Japan. Reproductive medicine and biology. 2010 Mar; [PubMed PMID: 29662423]|
|||Jessup RL, Interdisciplinary versus multidisciplinary care teams: do we understand the difference? Australian health review : a publication of the Australian Hospital Association. 2007 Aug; [PubMed PMID: 17669052]|
|||Chandrapal JC,Nielson S,Patel DP,Zhang C,Presson AP,Brant WO,Myers JB,Hotaling JM, Characterising the safety of clomiphene citrate in male patients through prostate-specific antigen, haematocrit, and testosterone levels. BJU international. 2016 Dec; [PubMed PMID: 27226135]|
|||Shi S,Hong T,Jiang F,Zhuang Y,Chen L,Huang X, Letrozole and human menopausal gonadotropin for ovulation induction in clomiphene resistance polycystic ovary syndrome patients: A randomized controlled study. Medicine. 2020 Jan; [PubMed PMID: 31977842]|
|||Teede HJ,Misso ML,Boyle JA,Garad RM,McAllister V,Downes L,Gibson M,Hart RJ,Rombauts L,Moran L,Dokras A,Laven J,Piltonen T,Rodgers RJ,Thondan M,Costello MF,Norman RJ, Translation and implementation of the Australian-led PCOS guideline: clinical summary and translation resources from the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. The Medical journal of Australia. 2018 Oct 1; [PubMed PMID: 30453865]|
|||Franik S,Kremer JA,Nelen WL,Farquhar C, Aromatase inhibitors for subfertile women with polycystic ovary syndrome. The Cochrane database of systematic reviews. 2014 Feb 24; [PubMed PMID: 24563180]|
|||Committee Opinion No. 663: Aromatase Inhibitors in Gynecologic Practice. Obstetrics and gynecology. 2016 Jun; [PubMed PMID: 27214191]|
|||Rezk M,Shaheen AE,Saif El-Nasr I, Clomiphene citrate combined with metformin versus letrozole for induction of ovulation in clomiphene-resistant polycystic ovary syndrome: a randomized clinical trial. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2018 Apr; [PubMed PMID: 29076376]|