Pharmacology: Mechanism of Action:
Human chorionic gonadotropin (hCG) exerts its effect through various mechanisms, which depend 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.
Human chorionic gonadotropin (hCG) is secreted by fused and differentiated syncytiotrophoblasts. In adult females with infertility, human chorionic gonadotropin acts similar to luteinizing hormone (LH). It also possesses minimal follicle-stimulating hormone (FSH) activity.
Human chorionic gonadotropin promotes the development and maintenance of the corpus luteum and the production of progesterone. Subsequent to hCG administration, final luteinization or maturation of the oocytes ensues and either ovulation can ensue for timed insemination techniques, or oocyte retrieval can take place for assisted reproductive technology (ART) procedures. Once pregnancy is established, endogenous hCG is normally secreted by the placenta to assist the continued secretion of female hormones and the corpus luteum.
Further, hCG is supposed to be involved in placentation through activities such as maintaining angiogenesis of the uterine vasculature and promoting differentiation of cytotrophoblasts into syncytiotrophoblasts. Ample evidences suggest roles for regular hCG in fostering implantation, preventing fetal rejection, coordinating uterine and fetal growth, and, potentially, growth and development of fetal organs.
In adult and adolescent men with hypogonadotropic hypogonadism, hCG acts similar to LH and stimulates testosterone production in the Leydig cells and spermatogenesis in the seminiferous tubules. Stimulation of androgen synthesis by hCG causes development of secondary sex characteristics in males, and also helps in normalization of serum testosterone levels. In male infants and children with cryptorchidism, hCG acts like LH and causes the Leydig cells of the testes to elicit a testosterone surge and induce the descent of palpable testes.
Use of hCG in infertility: Ovarian stimulation is commonly used alone or with assisted reproductive techniques (ART) in patients with anovulatory infertility and other causes of infertility. Different factors are presumed to influence reproductive outcomes when ART is applied. Apart from patient's age, timing of insemination in relation to ovulation is considered the most important predictive factor for treatment success. Since the advent, human chorionic gonadotropin (hCG) has been used to trigger ovulation. A study was conducted with the aim to ascertain the impact of hCG administration and luteinizing hormone surge on treatment outcomes in ART with or without ovarian stimulation. For the study, a retrospective analysis of 2000 treatment cycles; 637 timed intercourse
and 1363 intrauterine insemination cycles was performed. Clomiphene citrate or letrozole, alone or with follicle stimulating hormone were used as stimulation protocols. LH surge was considered when LH levels increased ≥200% over preceding two days. hCG was administered at a dose of 10,000 IU when required. Clinical pregnancy rate per cycle was the primary outcome of the study. LH surge was associated with better outcomes. Furthermore, it was appreciated that pregnancy rate was higher when hCG was administered.
There is no consensus on appropriate dose of urine-derived hCG for oocyte maturation before oocyte collection in in vitro fertilization. Doses of 2500 to 15000 IU have been used invariably.
Hoyos and colleagues conducted a study to understand the usefulness of low dose urine-hCG for effective oocyte maturation in assisted reproductive technique regardless of the body mass index (BMI). A group of 295 females who were previously subjected to in vitro fertilization/ intracytoplasmic sperm injection cycles were recruited for the study. Therapeutic cycles were categorized into 3 groups according to BMI; <25 consisting 136 females, 25 to <30 consisting 84 females and ≥30 consisting 75 females. Patients were administered 5000, 10000 or 15000 IU of urine derived hCG for the purpose of final oocyte maturation prior to oocyte collection. The primary and secondary endpoints of the study were clinical pregnancy rates and live birth rates, respectively. It was noted that serum hCG level at 12-24 hours (increasing trend) was associated with dose of urine-derived hCG administered to trigger ovulation; the results did not vary according to the BMI. The total number of developed follicles, follicles ≥14 mm and serum estradiol level on the day urine-derived hCG was administered were remarkably higher in patients receiving 5000 IU compared to 10000 IU or 15000 IU. Similar findings were observed for the number of oocytes collected, number of mature oocytes and number of fertilized oocytes. The clinical pregnancy rates and live birth rates were alike with different doses of urine-derived hCG (Table). Further, it was noted that only maternal age had an adverse impact on clinical pregnancy and live birth rates.
It was thus concluded that low dose urine-derived hCG was effective for oocyte maturation and associated with clinical pregnancy and live birth rate similar to other doses of hCG. (see table).
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Human chorionic gonadotrophin in cryptorchidism:
Medical therapy such as hCG has been used since long for the management of cryptorchidism.
Medical therapy may have an advantage over other therapies, for instance, if patient shows partial response to medical therapy with hCG, it may be repeated to obtain complete response. Further, it has been shown that hCG is more potent than luteinizing hormone-releasing hormone therapy in treatment of cryptorchidism. A study was conducted by Christiansen and colleagues to ascertain the impact of hCG, gonadotropin releasing hormone (GnRH) and placebo in males with cryptorchidism (unilateral or bilateral maldescended testes). A group of 155 males with bilateral and 88 males with unilateral cryptorchidism were enrolled in the study. The patients enrolled aged between 1 and 13 years. Patients were administered intramuscular injections of hCG twice weekly for 3 weeks whereas GnRH and placebo were administered intranasally. It was noted that the outcomes with hCG were superior to GnRH and placebo in patients with bilateral maldescended testes. Following hCG therapy, both testes descended in 25% males and improvement in the position of testes was noted in another 25% patients. In patients with unilateral maldescended testes, 14% males attained complete testicular descent compared to 3% and 0% with placebo and GnRH therapy. It was thus inferred that 25% patients with cryptorchidism achieved testes descent with hCG therapy thus substantiating the use of this therapy. However, the study results did not support the use of GnRH therapy for this indication. In another trial, a group of 128 pre-pubertal boys with unilateral or bilateral cryptorchidism were recruited to appreciate the role of hCG treatment. Patients were randomized to receive different intramuscular doses of hCG therapy twice weekly for 5 consecutive weeks according to the age of the patient; patients aged 1-4 years received 10 doses of 250 IU, 4-7 years received 10 doses of 500 IU, and 7-12 years received 10 doses of 1000 IU. Complete clinical response (complete descend of testes into the scrotum) was noted in 25% patients, and partial response denoted as distal movement of testes towards scrotum was noted in 32% males (Figure). The baseline plasma testosterone levels were 18±9 ng/dL that increased remarkably during hCG treatment to range between 344±185 to 640±288 ng/dL. However, these values did not differ remarkably between responders and partial responders. The results thus confirmed the effectiveness of hCG for treatment of cryptorchidism with minimal effective dose being 500 IU twice weekly for five consecutive weeks.
Hypogonadotropic hypogonadal and effectiveness of hCG therapy:
Hypogonadism resulting from primary testicular or secondary hypothalamic-pituitary dysfunction (hypogonadotropic) is associated with impairment in testicular function. The features of hypogonadotropic hypogonadism include androgen deficiency, and delay or termination of sexual maturation. The treatment of this disorder depends on the choice of an individual to preserve fertility. It is noted that sperm production is restored to nearly 50% of the normal level with hCG or follicle stimulating hormone (FSH) therapy and full restoration is achieved with hCG plus FSH. Gonadotropin may be initiated at a dose of 1000-2500 IU twice weekly for 8 to 12 weeks.
It is noteworthy that hCG alone may be useful for inducing spermatogenesis in patients. (see figure).
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In a study, the importance of follicle stimulating hormone for spermatogenesis was ascertained in males with hypogonadotropic hypogonadism. Patients (n=13) with gonadotropin deficiency due to idiopathic hypogonadotropic hypogonadism, Kallmann syndrome or pituitary insufficiency were recruited in the study. Individuals were treated with GnRH or hCG for induction of spermatogenesis. When spermatogenesis was achieved individuals were treated with hCG alone for maintaining secondary sexual characteristics and to ascertain whether hCG alone could be useful to maintain sperm production. It was observed that after spermatogenesis, hCG therapy alone was continued for 3-24 months. After 12 months, sperm count started to decrease gradually but was present in all except one. On the basis of study observations, it could be inferred that once spermatogenesis is induced, it can be maintained for an extended duration with hCG alone.
Furthermore, it has been elicited that hCG has a stimulatory effect on testicular steroidogenesis and penile growth. In this context, a study conducted in a cohort of males with idiopathic hypogonadotropic hypogonadism with micropenis showed that administration of intramuscular injection of hCG thrice weekly for 8 weeks is useful for improving gonadal function and penile growth. Human chorionic gonadotropin helped in increasing serum testosterone level, penile length and testicular volume in males with idiopathic hypogonadotropic hypogonadism.
Human chorionic gonadotropin undergoes a series of metabolic conversions before ultimately being excreted in urine. One of the initial stages in hCG degradation is proteolytic cleavage of the β subunit (probably by human leukocyte elastase), which produces a 'nicked' form of the protein.
Nicked hCG rapidly dissociates into its component α and β subunits. Further, the nicked β subunit is degraded, mostly in the kidneys, resulting in a β-core fragment.
Human chorionic gonadotropin injections may be given intramuscularly (IM) or subcutaneously (SC). A large slew of studies have compared the pharmacokinetics of hCG after IM and SC administration, but the results obtained have been equivocal. A study by Saal et al revealed that compared with IM administration of hCG, peak serum drug concentration was remarkably delayed and serum half-life was prolonged after SC injection.
In another study, healthy pituitary-suppressed females were assigned to single hCG injections of 5000 and 10,000 IU IM and 10,000 IU SC. The average elimination half-life was 32-33
hours, regardless of the treatment regimen. Intramuscular and SC injections of 10,000 IU hCG were found to be bioequivalent with respect to AUC. The Cmax and Tmax were also similar between the two administration routes. Intramuscular doses of 5000 IU and 10,000 IU hCG were observed to be dose-proportional. It was thus concluded that since SC hCG is bioequivalent to IM hCG with respect to extent of absorption (its major pharmacokinetic variable) and is well tolerated, the SC administration route may be effectively and safely employed in assisted reproduction.