Pharmacological Classifications: Fertility Agent, Gonad-Stimulating Polypeptide Hormone
General Information: Human chorionic gonadotropin (HCG) and a recombinant formulation, called choriogonadotropin alfa (r-HCG), is a gonad-stimulating polypeptide hormone normally secreted by the placenta during pregnancy. The non-recombinant products are obtained from the urine of pregnant women. Recombinant-HCG is produced via recombinant DNA techniques in Chinese Hamster Ovary (CHO) cells. The pharmacological actions of HCG and of r-HCG are similar and resemble those of luteinizing hormone (LH); HCG is generally used as a substitute for LH. HCG has been used to treat cryptorchidism or hypogonadotropic hypogonadism in males, sometimes in combination with menotropins or follitropin. Interestingly, HCG was introduced for the treatment of cryptorchidism in 1931, and remained the only hormonal agent available to treat the condition until the 1970's, when gonadotropin-releasing hormone (GnRH) analogs also became a treatment option. Human chorionic gonadotropin (HCG) is used in controlled ovarian hyperstimulation protocols for infertility in females. Intralesional HCG has been utilized for the treatment of Kaposi's sarcoma, but further clinical trials are required to prove efficacy. Human chorionic gonadotropin is banned from use in competitive sport; some male athletes have used HCG to stimulate testosterone production or to prevent testicular atrophy resulting from the abuse of anabolic steroids and androgens. Urine-derived HCG was first approved by the FDA in 1939, and received subsequent approval for additional indications in 1973.
Mechanism of Action: The mechanism of action of human chorionic gonadotropin (HCG) depends upon the purpose for which it is being used, the sex of the patient, and the level of maturity of the patient to whom it is administered.
Adult females: In select females with infertility , human chorionic gonadotropin has actions essentially identical to those of luteinizing hormone (LH). Human chorionic gonadotropin (HCG) also appears to have additional, though minimal, follicle-stimulating hormone (FSH) activity. By administering HCG after follitropin, menotropins, or clomiphene, the normal LH surge that precedes ovulation can be mimicked. Human chorionic gonadotropin (HCG) promotes the development and maintenance of the corpus lutetium and the production of progesterone. Following HCG administration, final luteinization or maturation of the oocytes occurs and either ovulation can ensue for timed insemination techniques, or oocyte retrieval can take place for assisted reproductive technology (ART) procedures such as in vitro fertilization (IVF). Once pregnancy takes place, endogenous HCG is normally secreted by the placenta to support the continued secretion of female hormones and the corpus luteum.
Adult and adolescent males: In adult and adolescent men with hypogonadotropic hypogonadism, HCG acts like LH and stimulates testosterone production in the Leydig cells and spermatogenesis in the seminiferous tubules. Stimulation of androgen production by HCG causes development of secondary sex characteristics in males (e.g., deepening of voice, facial hair, etc.). Human chorionic gonadotropin (HCG) also stimulates the Leydig cells to produce estrogens; increased estrogen levels may produce gynecomastia in some males. Once HCG is initiated, it takes at least 70—80 days for germ cells to reach the spermatozoal stage. Response to treatment is also noted by the development of masculine features and the normalization of serum testosterone levels. Induction of testicular growth and increased sperm volumes may help to restore fertility in these men after many months to years of treatment, which is then sometimes combined with the use of either menotropins or follitropin.
Male infants and children: In the male infant, normal testicular descent is complete by 3 months of age. Testicular descent occurs secondary to an endogenous testosterone surge stimulated by pituitary gonadotropins in response to the discontinued exposure to maternal circulating estrogens upon birth; this testosterone surge peaks within 60 days postnatally. In male infants and children with cryptorchidism, HCG acts like LH and causes the Leydig cells of the testes to produce a testosterone surge and induce the descent of palpable testes. The hormonal stimulation by HCG may result in an early pseudopuberty, and in some cases, the response to hormonal therapy may be temporary in 10—20% of cases. Hormonal therapies like HCG have not replaced the primary surgical treatment for the condition, which is orchiopexy within the first 1—2 years of life. Early animal studies have suggested that HCG may be used as an adjunct to orchiopexy to help preserve fertility, but human data is lacking.1
Activity on body composition (all sexes): Human chorionic gonadotropin has no known effects on appetite, or on mobilization or distribution of body fat. It is not an effective treatment for obesity. In sport, athletes use HCG as an 'undetectable' anabolic steroid; HCG increases the body's production of testosterone and epitestosterone without increasing the ratio of the two hormones in the urine above normal values. Urinary testing is being developed which should allow for discriminate testing of HCG doping in sport.
Pharmacokinetics: Human chorionic gonadotropin is administered subcutaneously and intramuscularly. Similar to other polypeptides, gonadotropins are almost completely degraded in the gastrointestinal tract; therefore, parenteral administration is required.
Urine-derived products: In the body, human chorionic gonadotropin primarily distributes into the testes in males and into the ovaries in females. In the ovaries, HCG is concentrated in the fluid of the developing follicles. The metabolic fate of HCG has not been elucidated, but it is eliminated in a biphasic manner. The terminal half-life is approximately 23 hours. After a single IM injection, roughly 10—12% of a dose is excreted unchanged in the urine within 24 hours and can be detected for up to 3—4 days.
Route-Specific Pharmacokinetics: Intramuscular Route: Urinary-derived human chorionic gonadotropin (HCG) is administered by the intramuscular (IM) route; however, one study has shown similar bioavailability with subcutaneous (SC) administration.2 Subjective observations in the literature have also supported the use of HCG by the SC route as equivalent to IM administration clinically.3 Serum concentrations of HCG are detectable within 2 hours of IM administration; peak concentrations are attained within 6 hours and persist for roughly 36 hours.
Subcutaneous Route: Urinary-derived human chorionic gonadotropin (HCG) is administered by the intramuscular (IM) route; however, one study has shown similar bioavailability with subcutaneous (SC) administration.2 Subjective observations in the literature have also supported the use of HCG by the SC route as equivalent to IM administration clinically.3
Special Populations: Hepatic Impairment: The pharmacokinetics, safety, and efficacy of human chorionic gonadotropin have not been established in patients with hepatic impairment.4
Renal Impairment: The pharmacokinetics, safety, and efficacy of human chorionic gonadotropin have not been established in patients with renal impairment.4
Indications: Human chorionic gonadotropin (HCG) is indicated for different reasons in men and women. HCG is used in combination with other fertility drugs to increase a woman’s chance of pregnancy. In men or adolescent boys, HCG helps with the production of testosterone and sperm. HCG is also used in male children with cryptorchidism, a specific birth problem of the testes.
For the treatment of male infants and children with prepubertal cryptorchidism not caused by anatomical obstruction:
NOTE: HCG appears to be more effective at inducing testicular descent in those infants and children with palpable testes in the high scrotal, prescrotal, or inguinal regions. Intra-abdominal testes are especially refractory to HCG treatment. While hormonal therapy is traditionally instituted after the age of 4 years, there are several studies that include male children of younger ages, and there is some evidence that treatment prior to age 2 years may be beneficial in terms of long-term outcomes.5 Consult specialized references for the most current recommendations.
Children (males) >= 6 years: The International Health Foundation has advocated a dosage of 1000 USP units IM 2 times per week for a total of 5 weeks.1 NOTE: various dosage regimens have been advocated for male children >= 4 years old. The following alternative regimens have been employed; however, the total dosage and length of the treatment course may vary widely: 1) 4000 USP units IM 3 times per week for 3 weeks; 2) 5000 USP units IM every other day for 4 doses; 3) 15 doses of 500—1000 USP units IM given over a period of 6 weeks; or 4) administer 500 USP units IM 3 times per week for 4—6 weeks. If not successful, then another course of HCG 1 month later may be administered at doses of 1000 USP units IM 3 times per week for 4—6 weeks.
Children (males) 1—5 years: The International Health Foundation has advocated a dosage of 500 USP units IM 2 times per week for a total of 5 weeks.1
Infants (males) 6—12 months: The International Health Foundation has advocated a dosage of 250 USP units IM 2 times per week for a total of 5 weeks.1
For the treatment of select cases of hypogonadotropic hypogonadism:
•for the routine treatment of hypogonadotropic hypogonadism in adult and adolescent males:
Intramuscular or Subcutaneous dosage:
Adults and Adolescent males: NOTE: various dosage regimens have been advocated. The following alternative regimens have been employed; however, the total dosage and length of the treatment course may vary widely: 1) 500—1000 USP units IM or subcutaneous 3 times per week for 3 weeks, followed by the same dose twice per week for 3 weeks; 2) 4000 USP units IM or subcutaneous 3 times per week for 6—9 months, then reduced to 2000 USP units 3 times a week for an additional 3 months; or 3) HCG 2500 units subcutaneous 2 times per week in combination with FSH 150 International Units subcutaneous 3 times per week for at least 6 months.
•for the stimulation of spermatogenesis in males with primary or secondary hypogonadotropic hypogonadism and resultant oligospermia:
NOTE: Pretreatment with human chorionic gonadotropin (HCG) is required prior to combination treatment with menotropins or follitropin. Various dosage regimens have been advocated.
Intramuscular or Subcutaneous dosage (pretreatment with HCG):
Adult males: Pretreatment with 1000—2250 USP units IM/subcutaneous 2—3 times per week; dosages up to 5000 USP units of HCG IM 3 times per week. Administer until normal serum testosterone concentrations are achieved and masculinization (development of secondary sex characteristics) occurs. Pretreatment may require 4—6 months, followed by combined therapy with menotropins (hMg) or follitropin (r-hFSH). See the following regimens. In some patients with appropriate testicular volumes (i.e., > 4 mL), HCG treatment alone may produce adequate spermatogenesis.
Intramuscular or Subcutaneous dosage (HCG combined with menotropins therapy following HCG pretreatment):
Adult males: NOTE: various dosage regimens have been advocated. The following alternative regimens have been employed; however, the total dosage and length of the treatment course may vary widely. ONE REGIMEN: HCG 1000—1500 USP units administered IM/subcutaneous in combination with menotropins 75—150 International Units IM/subcutaneous. Both are administered every other day, but at separate sites. Combination therapy should be continued for at least 4 months to ensure detection of spermatozoa in the ejaculate and to increase testicular volume. Most men in clinical trials to date are noted to have sperm output by 6 months; target goals are reached with a median 9 months of treatment. ALTERNATIVE REGIMEN: HCG 2000 USP units administered IM/subcutaneous 2 times per week in combination with menotropins 75 International Units IM/subcutaneous given 3 times per week at a separate injection site. Combination therapy should be continued for at least 4 months to ensure detection of spermatozoa in the ejaculate. If an increase in spermatogenesis has not occurred in 4 months, the dosage of menotropins can be increased to 150 International Units IM 3 times per week or continued while the dose of HCG remains the same.
Intramuscular or Subcutaneous dosage (HCG combined with follitropin-alfa, FSH therapy following HCG pretreatment):
Adult males: FSH must be given in conjunction with hCG. Both drugs are administered roughly 3 times per week (i.e., every other day) but at separate sites. The recommended dose is HCG 1000—1500 USP units (or the dose required to maintain normal serum testosterone) administered IM or subcutaneous 3 times per week in combination with follitropin-alfa 150 International Units subcutaneous 3 times per week at different sites. The lowest dose of FSH which induces spermatogenesis should be utilized. If azoospermia persists, the dose of FSH may be increased to a maximum dose of 300 International Units 3 times per week. Combination therapy should be continued for at least 4 months to ensure detection of spermatozoa in the ejaculate and to increase testicular volume. Most men in clinical trials to date were noted to have sperm output by 6 months; target goals adequate for fertilization are reached with a median 9 months of treatment. The drugs may need to be administered for up to 18 months to achieve adequate spermatogenesis.
Subcutaneous dosage (HCG combined with follitropin-beta, FSH therapy following HCG pretreatment):
Adult males: FSH must be given in conjunction with hCG. Initially, give hCG 1500 International Units subcutaneous twice per week. If serum testosterone concentrations have not normalized after 8 weeks, the hCG dose may be increased to 3000 International Units subcutaneous twice per week. Give hCG at the dose needed to normalize serum testosterone concentrations in combination with follitropin-beta 225 International Units subcutaneous twice weekly or 150 International Units subcutaneous 3 times per week.67
For adjunctive treatment of anovulation in females with infertility not due to primary ovarian failure, including in women undergoing assisted reproductive technology (ART):
NOTE: HCG must be withheld if there is an excessive ovarian response, as evidenced by abnormally enlarged ovaries, multiple follicular development, or excessive estradiol production. Consult specialized references.
•for induction of ovulation in females treated with clomiphene who have an appropriate follicular response but a failure to ovulate:
Adult females: 5000—10,000 USP units of HCG IM as a single dose at the appropriate day, as determined by exam and ultrasound, after the last dose of clomiphene (usually 3—4 days after the last clomiphene dose).
•for induction of ovulation following treatment with menotropins or follitropin in females with infertility:
Adult females: 5000—10,000 USP units of HCG IM as a single dose 1 day after the last dose of menotropins or FSH pre-treatment. The labeling for menotropins recommends an HCG dosage of 10,000 USP units for anovulation.
•for luteal phase support† of infertile female patients with hypogonadotropic hypogonadism after they have completed a typical ovulation induction protocol with FSH/LH (menotropins):
Adult females: 2500 USP units of HCG IM given as a single dose 8 days after the initial dose of HCG was given.
•for induction of final oocyte maturation in preparation for oocyte harvest in females undergoing IVF or other ART procedures following follitropin treatment:
Adult females: When a sufficient number of follicles of adequate size are present with FSH therapy, FSH is discontinued and the final maturation of the follicles is induced by administering 5000—10,000 USP units of HCG IM as a single dose 1 day after the last dose of FSH. Oocyte retrieval is usually performed 34—36 hours later, before ovulation can occur.
Maximum Dosage Limits
No specific maximum dosage limit recommendations are available. Dosage regimens of urine-derived human chorionic gonadotropin (HCG) depend upon the patient's age, sex, weight, condition being treated, product chosen, and the prescribing clinician's judgment. Therefore, doses may vary widely and must be carefully individualized.
Contraindications and Precautions: Your health care provider needs to know if you have any of these conditions: asthma; cyst on the ovary; heart disease; migraine; kidney disease; ovarian cancer or other female-related cancer; prostate cancer or other male-related cancer; seizures; an unusual or allergic reaction to HCG or other products; pregnant; breast-feeding. Your healthcare provider will monitor treatment, including urine samples, blood tests, or ultrasound exams. If you think you have become pregnant, contact your healthcare provider at once.
Human chorionic gonadotropin, HCG is contraindicated for use in any patient with a prior history of HCG hypersensitivity. Choriogonadotropin alfa (r-HCG) is contraindicated in patients who have previously demonstrated hamster protein hypersensitivity. r-HCG is manufactured using Chinese hamster ovary cells.
Certain urine-derived human chorionic gonadotropin, HCG products are packaged with diluents containing Bacteriostatic Water for Injection, USP (i.e., contains benzyl alcohol).89 Such diluents should be used cautiously in any patient with a history of benzyl alcohol hypersensitivity. Benzyl alcohol has been associated with a fatal 'gasping syndrome' in neonates and premature infants and therefore diluents containing benzyl alcohol should be avoided in these populations.
The safety and effectiveness of human chorionic gonadotropin in children have not been established except as stated for the treatment of male children with cryptorchidism not due to anatomic obstruction. While the manufacturers do not recommend HCG for this use in male children under the age of 4 years, the literature describes HCG treatment protocols in younger children. Consult specialized references for the most current recommendations. Human chorionic gonadotropin, HCG may induce precocious puberty in males treated for cryptorchidism. This risk should be balanced against the expected benefit from the treatment (see Adverse Reactions). HCG is contraindicated in patients with precocious puberty.89
Human chorionic gonadotropin, HCG induces androgen secretion, which can result in fluid retention. Human chorionic gonadotropin should be used with caution in patients with health problems that may be exacerbated by fluid retention, including some patients with asthma, cardiac disease, renal disease, seizure disorder, or migraine headache. Rarely, thromboembolic events have been reported in females receiving medications for controlled ovarian hyperstimulation protocols. HCG should be used extremely cautiously in those patients with active thrombophlebitis or other active thromboembolic disease. Caution is also warranted in patients with risk factors of thromboembolic events such as prior medical or family history.4 Similar warnings have not been issued for the treatment of hypogonadism or cryptorchidism in males.
Because of induction of androgen and other hormone secretion, HCG is contraindicated in males with prostate cancer, or any patient with sex hormone-dependent neoplastic disease. Because fertility protocols that include HCG may stimulate the growth of hormone-dependent tissues, HCG administration should be used cautiously in females with abnormal ordysfunctional uterine bleeding or vaginal bleeding of undetermined origin. Neoplastic disease of the reproductive tract and accessory organs (e.g., ovarian cancer or endometrial cancer) should be ruled out before use in females. Endometrial growth may be stimulated by these fertility protocols; they should be used cautiously in patients with uterine leiomyomata (fibroids) or endometriosis. It has been suggested that the use of fertility drugs might increase the risk of certain cancers in females. Some observational studies and a number of case reports gave rise to the speculation that the increased number of ovulatory follicles and/or high gonadotropin and estrogen levels induced by infertility treatment might enhance the development of breast or ovarian cancer. However, infertility alone is an independent risk factor for the development of either breast or ovarian cancer. Case reports also rarely control for other independent confounding factors such as delay in parity or family history. In one long-term cohort study of 1,197 infertile women, the incidence of ovarian or breast cancer was not significantly elevated in the groups receiving fertility treatments versus those not treated. The breast cancer rate, in particular, was not significantly different in either group versus the general female population. While more studies are needed, current data do not support an association between the use of fertility drugs and increased cancer risks.10
Females who are determined to have primary ovarian failure are not candidates for infertility treatment protocols that call for ovarian hyperstimulation (e.g., clomiphene, menotropins, or follitropin followed by HCG administration). Ovarian hyperstimulation protocols will only be effective for assisted reproduction in women with an intact ovarian response. Patients with uncontrolled organic intracranial lesions such as pituitary adenoma or other pituitary tumor, uncontrolled thyroid disease or untreated adrenal insufficiency should also not receive HCG.
Prior to initiation of HCG administration in women undergoing controlled ovarian hyperstimulation, a full gynecologic exam should be performed, including a pelvic ultrasound, to detect the appropriate progression of follicular development and the absence of inappropriate ovarian enlargement. HCG should not be administered to patients with ovarian enlargement or a preexisting ovarian cyst. HCG therapy should not be initiated until the diagnostic cause of the cyst or enlargement has been determined and ovary size has returned to normal. All female patients undergoing controlled ovarian hyperstimulation should be instructed to report symptoms of ovarian enlargement, including abdominal pain or pelvic pain; nausea; vomiting; ascites (fluid and distension in the abdomen); or weight gain immediately. The current cycle of fertility agents should be halted if ovarian enlargement or ovarian hyperstimulation syndrome (OHSS) occurs or if an ovarian cyst develops; maximal ovarian enlargement may not be evident until several days after fertility drug discontinuation. HCG administration should not occur in these patients. However, withholding of HCG does not ensure that OHSS will not occur. Fertility therapy should not be reinstated until ovary size has returned to normal. Complete pelvic exams, including pelvic ultrasounds, should be repeated in all female patients during and prior to each fertility drug cycle. Some patients with polycystic ovary syndrome (PCOS) are unusually sensitive to gonadotropins and may have an exaggerated response to ovarian hyperstimulation protocols.
Clinical studies of HCG for the treatment of infertility in women typically do not include a sufficient number of geriatric females. Use with caution in elderly females who are undergoing assisted reproductive technology (ART) procedures.
Human chorionic gonadotropin is used for infertility treatments and is classified in FDA pregnancy category X and is contraindicated after conception has occurred. When administered to mice, animal derived formulations of exogenous HCG have induced a high incidence of external congenital anomalies. While animal data are not always indicative of the response in human gestation, the potential for serious fetal harm cannot be excluded. Therefore, pregnancy should be ruled out prior to the administration of HCG with each fertility treatment course. In addition to potential effects on the fetus, protocols using HCG inherently increase the risk of multiple gestation and the risks associated with such pregnancies.48
Human chorionic gonadotropin, HCG should be used with caution in lactating women who are breast-feeding. Most endogenous gonadotropins are found in breast milk or tissues to some degree. It is neither known whether exogenous HCG is distributed into breast milk, nor what effect this would have on the breast-feeding infant.48
Due to the lack of therapeutic effect and potential risks of therapy, human chorionic gonadotropin, HCG is not to be used for the treatment of obesity. Claims that HCG increases weight loss beyond that from calorie restriction, that it causes a more attractive or normal distribution of fat, or that it decreases the hunger and discomfort associated with calorie restricted diets are not supported by substantial evidence. Numerous data to date suggest the agent is not effective in assisting weight loss.89
Drinking alcoholic beverages, including ethanol intoxication, or tobacco smoking are two lifestyle choices that may decrease fertility or the effectiveness of fertility treatments in some women and/or men. Patients should avoid excessive alcohol or tobacco consumption while pursuing fertility therapies like HCG.
Safety and efficacy of HCG has not been determined in patients with renal impairment or hepatic disease. In clinical evaluation of recombinant choriogonadotropin alfa injection, elevations in ALT were found in 10 (3%) of 335 patients receiving a 250 mcg dose, 9 (10%) of 89 patients receiving a 500 mcg dose, and in 16 (4.8%) of 328 patients receiving urine-derived HCG. Elevations in ALT ranged up to 1.2 times the upper limit of normal. At this time, the clinical significance of these findings is unknown.4
This list may not include all possible contraindications.
Pregnancy: Human chorionic gonadotropin is used for infertility treatments and is classified in FDA pregnancy category X and is contraindicated after conception has occurred. When administered to mice, animal derived formulations of exogenous HCG have induced a high incidence of external congenital anomalies. While animal data are not always indicative of the response in human gestation, the potential for serious fetal harm cannot be excluded. Therefore, pregnancy should be ruled out prior to the administration of HCG with each fertility treatment course. In addition to potential effects on the fetus, protocols using HCG inherently increase the risk of multiple gestation and the risks associated with such pregnancies.48
Breast-feeding: Human chorionic gonadotropin, HCG should be used with caution in lactating women who are breast-feeding. Most endogenous gonadotropins are found in breast milk or tissues to some degree. It is neither known whether exogenous HCG is distributed into breast milk, nor what effect this would have on the breast-feeding infant.48
Interactions: Possible interactions include: herbal or dietary supplements, like blue cohosh, black cohosh, or chasteberry. This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use.
No drug-drug interactions studies have been conducted with HCG in humans.
Some herbal or alternative therapies may have effects on hypothalamic-pituitary function or hormone concentrations and thus may interfere with fertility therapies. Chasteberry, chaste tree fruit, Vitex agnus-castus may interfere with the therapeutic activity of infertility drugs. A case of ovarian hyperstimulation syndrome and multiple follicular development has been reported in a woman who took chasteberry prior to one of her IVF protocol cycles; serum gonadotropin and hormone levels were disordered and pregnancy was not accomplished.11 Due to a lack of data, herbal therapies touted for women's health are not recommended for use with prescribed fertility treatments.
Black cohosh, Cimicifuga racemosa, is a phytomedicinal that may potentially suppress luteinizing hormone (LH).121314 It could potentially antagonize certain fertility agents that augment gonadotropin release. Due to a lack of data, any herbal therapies touted for women's health are not recommended for use with prescribed fertility treatments.
Adverse Reactions/Side Effects: What are some possible side effects of this medicine? Changes in emotions or mood, headache; pain, irritation or inflammation at the injection site; fatigue. This list may not describe all possible side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue. For boys: acne; breast enlargement; enlargement of penis and testes; development of facial or pubic hair; a sudden increase in height. For women on fertility treatments: indigestion; nausea, vomiting; passing small amounts of urine; shortness of breath; stomach area or pelvic pain or bloating; swelling; rapid weight gain.
Congenital abnormalities and spontaneous abortion have been reported subsequent to pregnancies resulting from HCG therapy in controlled clinical studies. However, the incidence of major congenital malformations is consistent with the reported rate for pregnancies resulting from natural or assisted conception. Human chorionic gonadotropin, HCG is contraindicated for use during pregnancy.4 Data suggest that teratogenesis might occur during organogenesis if HCG is inadvertently continued in early pregnancy. For example, animal studies reveal a possible connection of HCG administration with external congenital anomalies. It is important that HCG therapy be continued in subsequent fertility cycles only after pregnancy has been ruled out and normal withdrawal bleeding (menses) has occurred.
Infrequent reports of both benign and malignant ovarian neoplasms exist in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established.4 Some observational studies and a number of case reports gave rise to the speculation that infertility treatments might enhance the risk of secondary malignancy in women (i.e, breast cancer or ovarian cancer). However, infertility alone is an independent risk factor for the development of either breast or ovarian cancer. Case reports and observational studies suggesting an association of cancer to fertility treatments, like human chorionic gonadotropin, HCG, rarely control for other independent confounding factors such as delay in parity or family history. In one long-term cohort study of 1,197 infertile women, the incidence of ovarian or breast cancer was not significantly elevated in the groups receiving fertility treatments versus those not treated. The breast cancer rate, in particular, was not significantly different in either group versus the general female population.10 While certainly more studies are needed, the current data do not support an association between the use of fertility drugs and increased cancer risk.
The use of human chorionic gonadotropin (HCG) at therapeutic doses is generally well tolerated when used as a single agent. The appearance of side effects related to HCG may vary with dosage administered, gender, and reason for therapeutic use. Reported side effects include edema, ectopic pregnancy (< 2%), breakthrough bleeding (< 2%), vaginitis (< 2%), leukorrhea (< 2%), and vaginal bleeding (< 2%).9
An injection site reaction may occur with human chorionic gonadotropin, HCG and commonly includes pain and mild erythema, particularly with intramuscular administration. In some protocols, patient acceptability of injections is improved with subcutaneous injections. After SC administration, 14 to 16.2% of patients experienced an injection site reaction including 7.6—8.1% with injection site pain, 3—4.7% with injection site bruising, 2% with injection site inflammation, and 3% with an unspecified injection site reaction. Injection site reactions have also been reported after IM administration.49
Both localized and systemic hypersensitivity reactions have been reported with human chorionic gonadotropin, HCG.Hypersensitivity reactions have included angioedema, anaphylactic shock, anaphylactoid reactions, dyspnea or shortness of breath, erythema, rash (unspecified) (< 2%), pruritus (< 2%), and urticaria. Post-marketing surveillance of choriogonadotropin alfa injection revealed cases of allergic reactions, including anaphylactoid reactions and mild reversible skin rashes; causal relationship is not known.49
Mastalgia (< 2%) and gynecomastia have been reported as adverse effects of human chorionic gonadotropin, HCG.9 Adult and adolescent men may complain of gynecomastia with HCG use, and the complaint may occur in up to 30% of patients treated. The mechanism underlying the gynecomastia is thought to be due to the secretion of estrogen from the Leydig cells in response to HCG. The lowest dosage of HCG that maintains the patient's serum testosterone levels within the normal range may be helpful in limiting this unwanted side effect.
Precocious puberty can develop in prepubertal male children receiving human chorionic gonadotropin, HCG for treatment of cryptorchidism because of androgen secretion induction by HCG. Acne, phallic and testicular enlargement, aggressive behavior or agitation, early development of pubic hair, and rapid increase in height characterize precocious puberty. Human chorionic gonadotropin, HCG therapy generally requires discontinuation if precocious puberty occurs.9 Changes are usually reversible within 4 weeks of the last dose of HCG.
Depression is a reported side effect of human chorionic gonadotropin, HCG.9 Also, headache, hot flashes, dizziness, malaise, emotional lability, and insomnia were each noted in < 2% of patients. Fatigue, irritability, and restlessness were also reported.49
In trials with human chorionic gonadotropin, HCG, 3—4.2% had abdominal pain, 3.4% had nausea, 2.5% had vomiting, and < 2% had diarrhea, flatulence, or back pain. Some of the adverse events may also be signs of the ovarian hyperstimulation syndrome.
The following discusses adverse effects that are related to the use of controlled ovarian hyperstimulation protocols in which HCG may be used as an adjunct to clomiphene, follitropin, or menotropins in females. Mild to moderate uncomplicated ovarian enlargement, which may be accompanied by abdominal distention and/or abdominal pain, may occur in patients treated with FSH and HCG and generally regresses without treatment within two or three weeks. Careful monitoring of ovarian response can further minimize the risk of overstimulation. In trials, 3% had ovarian enlargement. In addition to ovarian enlargement, ovarian cysts (3%) may occur.49 Pelvic examination and ultrasound should be performed in patients who complain of abdominal discomfort (pelvic pain) during therapy. If enlargement or cysts are present, the current fertility treatment cycle should be discontinued and further therapy withheld until resolution of the signs and symptoms and until the ovary is no longer enlarged. If substantial ovarian enlargement occurs after ovulation, sexual intercourse should be prohibited because of the risk of hemoperitoneum secondary to ruptured ovarian cysts. Human chorionic gonadotropin, HCG should be withheld if ovarian enlargement is present on the last day of FSH therapy in order to reduce the risk of ovarian hyperstimulation. Most ovarian cysts or enlargements will regress within a few days to weeks after discontinuation of the fertility medications. Laparoscopy is rarely needed. Ovarian enlargement or ovarian cyst formation may be more likely to occur in patients with polycystic ovary syndrome.
Follow patients for at least two weeks after HCG administration. Most often, ovarian hyperstimulation syndrome (OHSS) occurs after treatment has been discontinued and reaches its maximum at about seven to ten days after treatment. Usually, OHSS resolves spontaneously with the onset of menses. If severe OHSS occurs, stop treatment with gonadotropins and hospitalize the patient. The pathogenesis of this syndrome is still unknown but probably results from the production and secretion of several substances (i.e., prostaglandin, cytokines, vascular endothelial growth factor, and activation of the ovarian-renin-angiotensin system) in response to the stimulation of ovulation. Patients have exhibited increased plasma angiotensin-converting enzyme (ACE) activity in association with this syndrome. Some early warning signs include severe abdominal pain and distention, pelvic pain, nausea/vomiting, diarrhea, and weight gain. Severe cases produce clinical signs such as gross ovarian enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural effusion. Other reported symptoms of OHSS include pericardial effusion, anasarca, hydrothorax, acute abdomen, elevated transaminases, hypotension, renal failure (unspecified), pulmonary edema, intraperitoneal (hemoperitoneum) and ovarian hemorrhage, thrombus formation, stroke, torsion of the ovary, and acute respiratory distress. Elevated urinary steroid levels, electrolyte imbalance, hypovolemia, hemoconcentration, and hypoalbuminemia may also occur. Hemoconcentration, hypovolemic shock, or thrombotic events may be fatal.4 Abdominal and pelvic examination should be done carefully in severe cases of OHSS due to the fragility of the enlarged ovaries. HCG and other fertility therapies should not be reinstated until ovary size has returned to normal. Conception may result in progression to the severe form of OHSS.
In clinical evaluation of recombinant choriogonadotropin alfa injection, elevated hepatic enzymes were reported. Elevations in ALT were found in 10 (3%) of 335 patients receiving a 250 mcg dose, 9 (10%) of 89 patients receiving a 500 mcg dose, and in 16 (4.8%) of 328 patients receiving urine-derived HCG. Elevations in ALT ranged up to 1.2 times the upper limit of normal. At this time, the clinical significance of these findings is unknown. Also, transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with ovarian hyperstimulation syndrome.4 Of note, the safety and efficacy of HCG has not been determined in patients with hepatic insufficiency.
Human chorionic gonadotropin, HCG may be associated with thrombosis such as arterial thromboembolism. Post-marketing surveillance of choriogonadotropin alfa injection has revealed cases of thromboembolic events both in association with and separate from the ovarian hyperstimulation syndrome; use with caution in patients with a history of thromboembolic disease.4
This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.
How is this medication best taken? This medicine is either injected into a muscle (intramuscular) or under the skin (subcutaneous). Ask your doctor which way is right for you. Use exactly as directed. Take your medicine at regular intervals. It is important that you put your used needles and syringes in a special sharps container. Do not put them in a trash can. If you do not have a sharps container, call your pharmacist or healthcare provider to get one. Talk to your pediatrician regarding the use of this medicine in children. While this drug may be prescribed for male children as young as several months of age for selected conditions, precautions apply. Follow proper Reconstitution Instructions included with the presctiption. The following are reconstitution instructions for HCG 3,000 IU, HCG 5,000 IU, HCG 11,000 IU, and HCG 50,000 IU.
What do I do if I miss a dose? If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take your next regularly scheduled dose. Do not take two doses at the same time.
Storage: Store dry powder at room temperature. Once reconstituted keep this medicine in a refrigerator below 41°F (5°C). Keep all medicine out of the reach of children. Throw away any unused medicine after the expiration date. Do not flush unused medications or pour down a sink or drain.
General Statements: Do not share or take any one else's medicine. Talk with your healthcare provider before starting any new medicine, including over-the-counter, natural products, or vitamins. This medication was compounded specifically for you. This patient information summarizes the most important information about your medication; if you would like more information, talk with your doctor.
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