Management of prepubertal cryptorchidism not caused by anatomical obstruction.
Induction of testicular descent usually only temporary; response may be permanent in some patients.
Differential diagnosis (hCG stimulatory test) of cryptorchidism in prepubertal boys to predict whether subsequent orchidopexy will be required. In general, hCG is thought to induce testicular descent in patients in whom descent would have occurred at puberty.
Start corrective therapy for cryptorchidism before pubescence to prevent irreparable testicular damage; opinions differ regarding optimum age for treatment. Manufacturers recommend instituting u-hCG therapy for prepubertal cryptorchidism in boys 4–9 years of age.
Stimulation of spermatogenesis in males with hypogonadotropic hypogonadism secondary to pituitary deficiency†. Full response may require concurrent FSH or menotropins therapy†.
Female Infertility
Used in conjunction with follicle-stimulating agent(s) (e.g., menotropins as fixed-combination preparations or separate components, FSH†) to induce ovulation in anovulatory, infertile women in whom anovulation is secondary (e.g., pituitary insufficiency).
Should not be used in infertile women in whom anovulation is due to primary ovarian failure.
Has been used for the treatment of infertility resulting from deficiency of corpus luteum during luteal phase of menstrual cycle†.
Other Uses
Manufacturer states that u-hCG has not been shown to be effective as adjunctive therapy for the treatment of obesity.
Dosage and Administration
General
Female Infertility
Should be prescribed only by clinicians experienced in infertility treatment and who are familiar with criteria for patient selection and cautions, precautions, and contraindications associated with hCG/follicle-stimulating therapy.
Administer follicle-stimulating agent(s) until sufficient follicular maturation (as determined by serum estradiol concentrations and ovary ultrasound examinations) occurs.
When ultrasound assessment and serum estradiol concentrations show sufficient follicular maturation, discontinue follicle-stimulating therapy and administer hCG to complete final follicular maturation and induce ovulation.
Withhold further follicle-stimulating therapy and delay or withhold hCG if ovaries show an excessive response to treatment with gonadotropins because of increased risk of ovarian hyperstimulation syndrome (OHSS). (See Ovarian Hyperstimulation Syndrome under Cautions.)
Encourage daily sexual intercourse beginning 1 day prior to administration of hCG until ovulation occurs (as determined by rise in basal body temperature, increase in serum progesterone concentrations, and menstruation following shift in basal body temperature). (See Adequate Patient Evaluation and Monitoring under Cautions.)
If stimulation of ovulation is unsuccessful, adjust dosage of follicle-stimulating agent administered in subsequent cycles based on woman’s response in preceding cycle.
Administration
IM Administration
Administer only by IM injection.
Reconstitution
Reconstitute vial containing 10,000 units of chorionic gonadotropin lyophilized powder with 10 mL of bacteriostatic water for injection or water for injection (provided by manufacturer).
Gently agitate until powder is completely dissolved.
Dosage
Dosage is expressed in terms of USP units (units). Each mg of u-hCG is approximately equivalent to ≥1500 USP units. One USP unit is equivalent to 1 WHO international unit.
Dosage regimens vary widely; individualize dosage carefully based on condition being treated, patient age and weight, and clinician’s judgment. Following treatment regimens suggested by various experts:
Pediatric Patients
Prepubertal Cryptorchidism
IM
Boys ≥4 years of age: 4000 units 3 times weekly for 3 weeks or 5000 units every other day for 4 doses or 15 doses of 500–1000 units given over 6 weeks suggested.
Alternatively, 500 units may be given 3 times weekly for 4–6 weeks for boys ≥4 years of age. If this course of therapy is not successful, may administer a subsequent course of therapy 1 month later and increase dosage to 1000 units 3 times weekly for 4–6 weeks.
Hypogonadotropic Hypogonadism in Males
IM
500–1000 units 3 times weekly for 3 weeks suggested, followed by same dosage twice weekly for 3 weeks.
Alternatively, 4000 units 3 times weekly for 6–9 months, followed by 2000 units 3 times weekly for 3 months.
Adults
Hypogonadotropic Hypogonadism in Males
IM
500–1000 units 3 times weekly for 3 weeks suggested, followed by same dosage 2 times weekly for 3 weeks.
Alternatively, 4000 units 3 times weekly for 6–9 months, followed by 2000 units 3 times weekly for 3 months.
Female Infertility
Ovulation Induction
IM
5000–10,000 units given 1 day following last dose of follicle-stimulating therapy suggested.
Risk of mild to moderate uncomplicated ovarian enlargement when used in conjunction with follicle-stimulating agent(s); may be accompanied by abdominal distention and/or pain but generally regresses without treatment within 2–3 weeks. Careful monitoring of ovarian response recommended.
If ovaries are abnormally enlarged, withhold hCG administration during current course of therapy to minimize risk of OHSS. (See Ovarian Hyperstimulation Syndrome under Cautions.)
Ovarian Hyperstimulation Syndrome
Risk of potentially severe OHSS, characterized by apparent dramatic increase in vascular permeability that may result in rapid accumulation of fluid in peritoneal cavity, thorax, and potentially, pericardium.
May progress rapidly (within 24 hours to several days) and is initially manifested by pelvic pain, nausea, vomiting, and weight gain. Other symptoms include abdominal pain/distention, diarrhea, severe ovarian enlargement, dyspnea, and oliguria. Hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events may occur.
Transient liver function test abnormalities, which may be accompanied by morphologic changes (as detected by liver biopsy), reported.
Occurs most often after completion of gonadotropin therapy, reaching maximum severity after 7–10 days; usually resolves spontaneously with onset of menses. Monitor patients for ≥2 weeks after hCG administration. OHSS may be more severe and protracted if pregnancy occurs.
If severe OHSS occurs, discontinue therapy, hospitalize patient, and consult clinician experienced in management of OHSS or fluid and electrolyte imbalances.
Multiple Births
Multiple ovulations resulting in multiple gestations reported in approximately 20% of women during ovulation induction.
Ovarian Cysts
Enlargement of preexisting ovarian cysts or rupture of ovarian cysts with resultant hemoperitoneum reported.
Thromboembolism
Arterial thromboembolism reported.
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity demonstrated in mice.
Exclude pregnancy before initiating treatment with hCG and menotropins. (See Contraindications under Cautions.)
Benzyl Alcohol in Neonates
Bacteriostatic water for injection or water for injection diluent contains benzyl alcohol as a preservative, which has been associated with toxicity (fatalities) in neonates. (See Pediatric Use under Cautions.)
General Precautions
Androgenic Effects
May cause fluid retention; use caution in patients with asthma, seizure disorders, migraine, or cardiac or renal disease.
Induction of precocious puberty may occur in prepubertal males with cryptorchidism. (See Pediatric Use under Cautions.)
Tumorigenic Effects
Testicular tumors reported occasionally in young men with secondary infertility.
Adequate Patient Evaluation and Monitoring
Administer only under supervision of qualified clinicians experienced in fertility disorders and interpretation of indices of ovulation.
Monitor follicular development (e.g., using ovarian ultrasound, serum estradiol concentrations) to correctly identify follicular maturation, determine timing of hCG administration, detect ovarian enlargement, and minimize risks of OHSS and multiple gestation.
Obtain clinical confirmation of ovulation from direct and indirect indices of progesterone production (e.g., rise in basal body temperature, increase in serum progesterone concentrations, menstruation following shift in basal body temperature). Sonographic evidence of ovulation includes findings of fluid in cul-de-sac, ovarian stigmata, collapsed follicle, and secretory endometrium.
Specific Populations
Pregnancy
Category X. (See Fetal/Neonatal Morbidity and Mortality and also Contraindications under Cautions.)
Lactation
Not known whether u-hCG is distributed into milk. Use caution.
Pediatric Use
Safety and efficacy not established in children <4 years of age.
Carefully monitor prepubertal males with cryptorchidism during u-hCG therapy since induction of precocious puberty may occur. If signs of precocious puberty (phallic enlargement, testicular enlargement and redness, development of pubic hair, aggressive behavior) occur, discontinue therapy; these signs are reversible ≤4 weeks after cessation of therapy. (See Contraindications under Cautions.)
Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) have been associated with toxicity (fatal “gasping syndrome”) in neonates; each multiple-dose vial of reconstituted drug contains 0.9% benzyl alcohol.
Geriatric Use
Safety and efficacy not established.
Common Adverse Effects
Headache, irritability, restlessness, depression, fatigue or tiredness, edema, precocious puberty, gynecomastia, pain at injection site.
Interactions
Laboratory Tests
Laboratory Test
Interaction
Comments
Radioimmunoassays for gonadotropins
Possible cross reaction with radioimmunoassays for gonadotropins, particularly LH
Individual laboratories should establish degree of cross reactivity with their gonadotropin assay
When requesting gonadotropin concentrations, inform laboratory of u-hCG therapy
Pharmacokinetics
Absorption
Onset
Following single injection in hypogonadotropic men, onset and peak stimulation of testosterone production (as indicated by plasma testosterone concentrations) occur at 24 and 80 hours, respectively.
Following single injection in prepubertal and early pubertal boys with cryptorchidism, peak stimulation of testosterone production occurs at 2–5 days.
Duration
Following midcycle administration, stimulation of luteal-phase progesterone production (as indicated by serum progesterone concentrations) persists for approximately 1 week. (See Actions.)
Following single injection in prepubertal boys with cryptorchidism, stimulation of testosterone production persists for ≥6 days.
Special Populations
Bioavailability is less in obese infertile women than in nonobese women.
Distribution
Extent
Distributed mainly into testes and ovaries; smaller amounts may be distributed into proximal tubules of renal cortex.
Not known if distributed into milk.
Elimination
Metabolism
Extensively metabolized, principally in liver and kidneys, to active metabolites.
Elimination Route
Excreted in urine (20%) as metabolites.
Half-life
Biphasic; terminal half-life is about 23–33 hours.
Stability
Storage
Parenteral
Powder for Injection
Pregnyl® or Novarel®: 15–30°C. After reconstitution, refrigerate at 2–8°C; use Novarel® within 30 days and Pregnyl® within 60 days.
Generic preparation: 20–25°C. After reconstitution, refrigerate at 2–8°C; use within 60 days.
Actions
Principal pharmacologic effects of u-hCG are virtually identical to those of LH; exhibits minimal FSH activity.
Stimulates differentiation of, and androgen production by, interstitial cells (Leydig cells) of the testes.
Stimulates differentiation of and early maturation of the cells lining the seminiferous tubules (spermatogenic and Sertoli cells) of the testes.
Stimulates spermatogenesis and increases testes volume.
Stimulates development of secondary sex characteristics in prepubertal males.
Induces aromatization of testosterone to estradiol in testes and peripherally; gynecomastia may occur.
Substitutes for the endogenous LH surge responsible for ovulation; stimulates late maturation of ovarian follicle, resumption of oocytic meiosis, and initiation of rupture of preovulatory ovarian follicle.
Induces and maintains corpus luteum (as evidenced by increased serum progesterone concentrations).
No known effect on appetite or sense of hunger, or on mobilization or distribution of body fat.
Advice to Patients
Importance of discussing duration of treatment and required monitoring procedures.
Importance of informing patient of potential adverse effects (e.g., OHSS, multiple gestation).
Importance of patients informing a clinician if severe pain or bloating in stomach or pelvic area, severe upset stomach, vomiting, or weight gain occurs.
Importance of patient informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of women informing their clinician if they plan to breast-feed.
Importance of informing patient of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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