Clomiphene Citrate, History, Mechanism of action, best Uses, Side effects, Dosage, & 5 Popular brands

Introduction

Clomiphene Citrate, commonly known by its brand names Clomid and Serophene, is a medication utilized in reproductive medicine. It falls into a class of drugs called selective estrogen receptor modulators (SERMs). This is primarily prescribed to treat infertility issues in women by stimulating the release of eggs from the ovaries. It can also be used off-label for various other medical conditions as determined by a doctor.

History

The history of Clomiphene Citrate is marked by significant milestones in the field of reproductive medicine and pharmaceutical development, reflecting its crucial role in treating infertility.

Discovery and Development

The journey of Clomiphene Citrate began in the 1950s when scientists at Merrell Company, later known as Sanofi, synthesized the compound while investigating potential estrogen modulators. Their research aimed to develop treatments for conditions related to hormonal imbalances by understanding and manipulating estrogen’s role in the body.

Clinical Trials and Approval

The initial research findings were promising, demonstrating that Clomiphene Citrate effectively stimulated ovulation in women with anovulatory infertility. Clinical trials in the late 1950s and early 1960s provided robust evidence of the drug’s efficacy and safety. These trials showed that Clomiphene Citrate could increase the production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by blocking estrogen receptors in the hypothalamus, thus promoting ovarian follicle development and ovulation.

In 1967, the U.S. Food and Drug Administration (FDA) approved Clomiphene Citrate for marketing under the brand name Hex. Initially, it was used to treat cases of oligomenorrhea, a condition characterized by infrequent menstrual periods. However, its application quickly expanded to include the treatment of anovulation when women undergoing Clomid treatment exhibited higher-than-expected pregnancy rates.

Widespread Use and Impact

Following its approval, Clomiphene Citrate became a cornerstone in managing female infertility, particularly for those with polycystic ovary syndrome (PCOS) and other conditions causing irregular or absent ovulation. Its oral administration, relatively low cost, and favorable safety profile contributed to its widespread adoption in clinical practice.

Expanding Applications

Over the years, the use of Clomiphene Citrate extended beyond female infertility. The drug has been used off-label to treat male infertility by stimulating endogenous testosterone production in men with certain types of hypogonadism. Additionally, it has been utilized in managing secondary amenorrhea and certain cases of unexplained infertility.

Clomiphene Citrate mechanism of action

Clomiphene Citrate, commonly known as Clomid, is a selective estrogen receptor modulator (SERM) that plays a crucial role in treating infertility, primarily by stimulating ovulation. Its mechanism of action is rooted in its ability to interact with estrogen receptors, leading to a cascade of hormonal events that promote ovulation. Here is a detailed overview of its mechanism of action:

1. Estrogen Receptor Antagonism: Clomiphene Citrate is an antagonist at estrogen receptors in the hypothalamus, a key brain region in hormone regulation. By blocking these receptors, Clomiphene Citrate creates the illusion of low estrogen levels in the body.
2. Increased Gonadotropin-Releasing Hormone (GnRH) Secretion: The perceived decrease in estrogen levels prompts the hypothalamus to increase the secretion of gonadotropin-releasing hormone (GnRH). GnRH is a critical hormone that stimulates the anterior pituitary gland to release gonadotropins.
3. Enhanced Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) Release: The increased GnRH levels lead to the secretion of higher amounts of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. FSH is essential for the growth and maturation of ovarian follicles, while LH plays a key role in triggering ovulation.
4. Ovarian Follicle Development: Elevated FSH levels stimulate the development and maturation of ovarian follicles. Multiple follicles begin to grow, although typically only one reaches full maturity and becomes the dominant follicle that is most likely to ovulate.
5. Ovulation Induction: As the dominant follicle matures, it produces increasing amounts of estrogen. When estrogen levels reach a certain threshold, they induce a positive feedback loop that causes a surge in LH secretion. This LH surge is the final trigger for ovulation, leading to the release of a mature egg from the dominant follicle.
6. Preparation for Fertilization: Following ovulation, the egg travels through the fallopian tube, where it can be fertilized by sperm. The corpus luteum, formed from the ruptured follicle, secretes progesterone to prepare the uterine lining for the potential implantation of a fertilized egg.

Through this intricate mechanism, Clomiphene Citrate effectively induces ovulation in women with ovulatory dysfunction, increasing their chances of conception. Its ability to modulate estrogen receptors and stimulate the hypothalamic-pituitary-ovarian axis underscores its vital role in fertility treatment.

Clomiphene Citrate uses

Clomiphene Citrate is a medication with several uses primarily within the field of reproductive medicine. Its main applications include:

Induction of Ovulation: Clomiphene Citrate is primarily used to induce ovulation in women with anovulatory or oligo-ovulatory infertility, particularly in conditions like polycystic ovary syndrome (PCOS). By stimulating the release of hormones necessary for ovulation, it helps regulate the menstrual cycle and increase the chances of pregnancy.

Treatment of Luteal Phase Defect: In some cases, this medicine is used to treat luteal phase defect, a condition where the second half of the menstrual cycle is shorter than normal, affecting the implantation and maintenance of early pregnancy. By improving ovulation, Clomiphene Citrate can enhance the quality of the luteal phase.

Assisted Reproductive Technologies (ART): It is also used as part of the protocol in assisted reproductive technologies such as in vitro fertilization (IVF) and intrauterine insemination (IUI). It helps stimulate the ovaries to produce multiple eggs, increasing the chances of successful fertilization and implantation.

Unexplained Infertility: For couples experiencing unexplained infertility, Clomiphene Citrate can be used to enhance fertility. Although the exact cause of infertility is unknown, inducing ovulation with Clomiphene Citrate can increase the likelihood of conception.

Male Infertility: Clomiphene Citrate is sometimes used off-label to treat male infertility. It can stimulate the production of gonadotropins, leading to increased testosterone levels and improved sperm production in men with certain types of hypogonadism or unexplained low sperm counts.

Secondary Amenorrhea: In women with secondary amenorrhea (absence of menstrual periods for six months or more in women who previously had regular cycles), Clomiphene Citrate is used to induce ovulation and restore regular menstrual cycles.

Diagnosis of Ovarian Reserve: It is occasionally used in tests to assess ovarian reserve, which is an indicator of a woman’s remaining egg supply. The response to Clomiphene Citrate can provide valuable information about ovarian function and fertility potential.

Clomiphene Citrate for Men

Clomiphene Citrate, commonly known as Clomid or Serophene, is used off-label to treat certain conditions of male infertility and hypogonadism. By blocking estrogen receptors in the hypothalamus, Clomiphene Citrate increases the secretion of gonadotropin-releasing hormone (GnRH), which stimulates the pituitary gland to produce more luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

This hormonal boost enhances the testes’ natural production of testosterone and supports spermatogenesis, potentially improving sperm count and quality. Unlike direct testosterone replacement therapy, which can suppress sperm production, Clomiphene Citrate helps maintain fertility while having low testosterone levels.

Clomiphene Citrate Dosage

The dosage of Clomiphene Citrate, commonly known as Clomid or Serophene, varies depending on the condition being treated and the individual patient’s response. Here is a detailed overview of the typical dosages for various uses:

For Female Infertility (Ovulation Induction)

Starting Dose: The usual starting dose for inducing ovulation in women is 50 mg per day for five consecutive days. This course typically begins on the fifth day of the menstrual cycle.

Adjustment: If ovulation does not occur, the dosage may be increased to 100 mg per day in subsequent cycles. The maximum recommended dosage is usually 150 mg per day.

Duration: Treatment can be repeated for up to six cycles. If ovulation does not occur after three cycles, further evaluation is needed.

For Male Infertility

Starting Dose: Clomiphene Citrate is used off-label to treat male infertility, with typical starting doses ranging from 25 mg to 50 mg per day or every other day.

Adjustment: The dosage may be adjusted based on the patient’s hormonal response (testosterone, LH, and FSH levels) and semen analysis results.

Duration: Treatment duration can vary, but it generally lasts for several months to assess its effectiveness on sperm production and testosterone levels.

Monitoring and Follow-Up

Regular Monitoring: Patients should undergo regular monitoring of hormone levels (FSH, LH, testosterone) and, for women, ovulation signs (basal body temperature, ovulation predictor kits, or ultrasound).

Side Effects: Both men and women should be monitored for potential side effects, such as headaches, visual disturbances, gastrointestinal discomfort, mood changes, and in women, ovarian hyperstimulation syndrome (OHSS).

General Guidelines

• Administration: Clomiphene Citrate is taken orally with or without food.
• Consistency: It should be taken at the same time each day to maintain consistent blood levels.

Special Considerations

• Medical Supervision: Clomiphene Citrate should be used under the supervision of a healthcare provider to ensure proper dosing, monitor side effects, and adjust treatment as needed.
• Contraindications: It is contraindicated in patients with liver disease, uncontrolled thyroid or adrenal disorders, abnormal uterine bleeding, and ovarian cysts, not due to polycystic ovarian syndrome (PCOS).

Clomiphene Citrate Side effects

Clomiphene Citrate, commonly known as Clomid or Serophene, is generally well-tolerated but can cause side effects in some individuals. The side effects can range from mild to severe, and it is important for patients to be aware of these potential reactions. Here are the most commonly reported side effects:

Common Side Effects

• Hot Flashes: Hot flashes or sudden feelings of warmth are one of the most frequently reported side effects.
• Abdominal Discomfort: Some individuals may experience bloating, abdominal pain, or discomfort, often due to ovarian enlargement.
• Breast Tenderness: Tenderness or pain in the breasts is a common side effect.
• Nausea and Vomiting: Mild nausea or vomiting may occur in some patients.
• Headaches: Headaches are commonly reported, though usually mild.
• Visual Disturbances: Blurred vision, spots, or flashes of light may occur, particularly at higher doses or with prolonged use. These symptoms typically resolve after discontinuation of the medication.

Less Common Side Effects

• Mood Changes: Some individuals may experience mood swings, irritability, or depression.
• Vaginal Dryness or Thickening of Cervical Mucus: These side effects can potentially impact fertility, as they might interfere with sperm transport.
• Fatigue and Dizziness: Some patients report feeling unusually tired or dizzy.

Serious Side Effects

• Ovarian Hyperstimulation Syndrome (OHSS): Although rare, OHSS can occur, particularly with higher doses or in women with polycystic ovary syndrome (PCOS). Symptoms include severe abdominal pain, swelling, shortness of breath, and rapid weight gain. This condition requires immediate medical attention.
• Multiple Pregnancies: Clomiphene Citrate increases the likelihood of multiple ovulations, leading to a higher risk of twins or triplets.
• Ovarian Cysts: The development of ovarian cysts can occur, which may cause pain or complications if they rupture.

Rare Side Effects

• Liver Dysfunction: Though extremely rare, liver function abnormalities have been reported.
• Thromboembolic Events: Very rarely, blood clots may occur, leading to serious complications like deep vein thrombosis or pulmonary embolism.

Considerations for Men

When used off-label for male infertility, side effects may include:

• Gynecomastia: Breast enlargement due to hormonal changes.
• Changes in Libido: Alterations in sexual desire.
• Headaches and Visual Disturbances: Similar to those experienced by women.

Precautions

While using Clomiphene Citrate it’s essential to be aware of certain Precautions.

Medical Supervision

Clomiphene Citrate should only be prescribed and monitored by a healthcare provider experienced in fertility treatments. Regular monitoring of hormone levels, ovarian response, and side effects is essential.

Ovarian Hyperstimulation Syndrome (OHSS)

Women treated with Clomiphene Citrate, especially those with polycystic ovary syndrome (PCOS), are at higher risk of developing OHSS. Symptoms include abdominal pain, bloating, nausea, vomiting, and rapid weight gain. Severe cases may require hospitalization.

Multiple Pregnancies

Clomiphene Citrate increases the likelihood of multiple pregnancies, including twins or higher-order multiples. Patients should be informed of the increased risks and complications associated with multiple gestations.

Ovarian Cysts

The medication can cause the development of ovarian cysts. These cysts may enlarge and, in rare cases, rupture, leading to potentially serious complications.

Visual Disturbances

Clomiphene Citrate may cause visual symptoms such as blurred vision, spots, or flashes. Patients experiencing these should discontinue the medication and seek medical evaluation promptly.

Pregnancy and Breastfeeding

Clomiphene Citrate should not be used during pregnancy. If pregnancy occurs, treatment should be discontinued immediately. It is not known whether Clomiphene Citrate passes into breast milk, so caution is advised if breastfeeding.

Warnings

While using Clomiphene Citrate it’s essential to be aware of certain Warnings.

Liver Function

Patients with pre-existing liver disease should use Clomiphene Citrate with caution. Liver function tests may be monitored periodically during treatment.

Thromboembolic Disorders

Rare cases of thromboembolic events, such as deep vein thrombosis and pulmonary embolism, have been reported with Clomiphene Citrate. Patients at risk or with a history of thromboembolic disorders should be closely monitored.

Endometrial Cancer Risk

Long-term use of Clomiphene Citrate may increase the risk of developing endometrial cancer. The duration of treatment should be limited to avoid this potential risk.

Psychiatric Effects

Clomiphene Citrate may cause mood swings, irritability, or depression. Patients with a history of psychiatric disorders should be monitored closely.

Hypersensitivity Reactions

Hypersensitivity reactions, including rash, itching, and swelling, have been reported with Clomiphene Citrate. Patients experiencing these symptoms should discontinue the medication and seek medical attention.

Drugs interactions

Clomiphene Citrate, commonly used for the treatment of infertility, can interact with various medications. Here are some potential interactions:

Estrogens

• Interaction: Clomiphene can interact with estrogen supplements, which might reduce its effectiveness.
• Reason: Both clomiphene and estrogens influence estrogen receptors, and using them together might diminish the stimulating effect of clomiphene on ovulation.

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Interaction: SSRIs, like fluoxetine and sertraline, can potentially interact with clomiphene.
• Reason: These medications can affect hormonal levels and may alter the ovulatory response to clomiphene.

Anticoagulants

• Interaction: Clomiphene may interact with anticoagulant medications like warfarin.
• Reason: Hormonal changes induced by clomiphene can potentially affect blood clotting parameters, necessitating closer monitoring of anticoagulant therapy.

Thyroid Hormones

• Interaction: Clomiphene can interact with thyroid hormone replacements such as levothyroxine.
• Reason: Both medications can influence each other’s efficacy, particularly in women with underlying thyroid disorders.

Corticosteroids

• Interaction: Corticosteroids like prednisone might interact with clomiphene.
• Reason: Corticosteroids can influence hormonal balance and the hypothalamic-pituitary-ovarian axis, possibly impacting clomiphene’s effectiveness.

Anti-Seizure Medications

• Interaction: Anti-seizure medications like phenytoin and carbamazepine may interact with clomiphene.
• Reason: These drugs can alter the metabolism of clomiphene, potentially reducing its effectiveness.

Gonadotropins

• Interaction: Gonadotropins used in fertility treatments can interact with clomiphene.
• Reason: These are often used together in controlled ovarian hyperstimulation protocols, but their interactions need careful monitoring to optimize treatment outcomes.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Interaction: NSAIDs like ibuprofen and naproxen might interact with clomiphene.
• Reason: NSAIDs can affect the endometrial lining and ovulation, potentially interfering with clomiphene’s action.

Clomiphene Citrate Price in Pakistan

Clomiphene Citrate also known as Clomid tablet 50mg which is available for Rs/ 628.86 in all Pharmacies in Pakistan.

Clomiphene Citrate brands name

Hex tablet 50mg– It is Manufactured by Stanley Pharmaceuticals Pvt Ltd

Clomid tablet 50mg– It is Manufactured by Sanofi Pharmaceuticals

Cerophene- It is Manufactured by Hilton Pharma

Ferticlo- It is Manufactured by Platinum Pharmaceuticals

Fertab- It is Manufactured by Shaigan Pharmaceuticals Pvt ltd