Human Chorionic Gonadotropin (hCG)

Number: 1081

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses human chorionic gonadotropin (hCG) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of Novarel (chorionic gonadotropin), Pregnyl (chorionic gonadotropin), Ovidrel (choriogonadotropin alfa), or chorionic gonadotropin is required of all Aetna participating providers and members in applicable plan designs. For precertification, call (866) 782-2779 or fax (860) 754-2515. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Medical/Pharmacy Benefit Alignment of Coverage for Infertility Drugs and Procedures:

Medical necessity review of infertility drugs by Aetna Specialty Pharmacy Guideline Management may be bypassed for infertility assisted reproductive technology (ART) drugs that are for use with infertility medical procedures if the infertility procedure has been approved for coverage under the member’s Aetna medical benefit plan. During precertification, a medical authorization number and confirmation of the approval of the infertility procedures will be required to bypass medical necessity review by Specialty Pharmacy Guideline Management. Note: Some plans may require medical necessity review of all infertility drugs by Aetna Specialty Guideline Management. Members of these plans must undergo Specialty Pharmacy Guideline Management medical necessity review of all infertility drugs regardless of whether the drugs are for use with approved infertility medical procedures. For additional information, see CPB 0327 - Infertility.

1. Criteria for Initial Approval

   Aetna considers human chorionic gonadotropin (hCG) (e.g., Novarel, Pregnyl, Ovidrel, generic) medically necessary for the following indications when criteria are met:

   1. Induction of oocyte maturation and/or release for members undergoing assisted reproductive technology (ART) or ovulation induction; or
   2. Prepubertal cryptorchidism treatment not due to anatomical obstruction; or
   3. Hypogonadotropic hypogonadism treatment in members who meet all of the following criteria:
      
      
      1. Member will be using the requested medication for the induction of spermatogenesis; and
      2. Member has at least two confirmed low pretreatment serum total testosterone levels based on the reference laboratory range or current practice guidelines, taken in the morning on separate days; and
      3. Member has low or low to normal follicle stimulating hormone (FSH) or luteinizing hormone (LH) levels; or

   4. Steroid-refractory acute graft-versus-host-disease (GVHD) when member meets either of the following:

      1. The requested medication will be taken in conjunction with systemic corticosteroids; or
      2. Member has an intolerance or contraindication to systemic corticosteroids.

   Note: Many plans that otherwise cover infertility treatments exclude coverage for infertility injectable medications.  Please check benefit plan descriptions.

   Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   Aetna considers continuation of hCG therapy medically necessary for all members (including new members) requesting reauthorization and meet all initial authorization criteria.

3. Related Policies 

   1. CPB 0001 - Transrectal Ultrasound
   2. CPB 0007 - Erectile Dysfunction
   3. CPB 0020 - Injectable Medications
   4. CPB 0170 - Growth Hormone (GH) and Growth Hormone Antagonists
   5. CPB 0327 - Infertility
   6. CPB 0345 - Implantable Hormone Pellets
   7. CPB 0501 - Gonadotropin-Releasing Hormone Analogs and Antagonists
   8. CPB 0528 - Testosterone Undecanoate (Aveed) Injection
   9. CPB 0532 - Scrotal Ultrasonography
   10. CPB 1014 - Testosterone Cypionate Injections
   11. CPB 1015 - Testosterone Enanthate Injection
   12. CPB 1082 - Follitropins and Menotropins

Dosage and Administration

The dosage regimen for hCG products used in any particular case will depend upon the indication for use, the age and weight of the individual, and the the physician's preference. Refer to the Full Prescribing Information of the requested product for additional information.

Experimental, Investigational, or Unproven 

Aetna considers the following indications experimental, investigational, or unproven because there is insufficient evidence for the use of hCG for these indications (not an all-inclusive list):

• Idiopathic male infertility (except for the medically necessary indications in Section I)
• Idiopathic microphallus 
• Treatment of obesity or weight loss management
• Use solely for endometrium preparation for frozen embryo transfer (FET) (see CPB 0327 - Infertility).

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
Spermatogenesis - No specific code
58974	Embryo transfer, intrauterine [hCG therapy not covered for use solely for endometrium preparation for frozen embryo transfer (FET)]
84403	Testosterone; total
84702	Gonadotropin, chorionic (hCG); quantitative
84703	qualitative
89255	Preparation of embryo for transfer (any method) [hCG therapy not covered for use solely for endometrium preparation for frozen embryo transfer (FET)]
HCPCS codes covered if selection criteria are met:
J0725	Injection, chorionic gonadotropin, per 1,000 usp units
ICD-10 codes covered if selection criteria are met (not all-inclusive):
D89.810	Acute graft-versus-host disease
E23.0	Hypopituitarism
G11.5	Hypomyelination - hypogonadotropic hypogonadism - hypodontia
Q53.00 - Q53.9	Undescended and ectopic testicle
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
E66.01 - E66.9	Overweight and obesity
Z68.1 - Z68.56	Body mass index (BMI)

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Chorionic gonadotropin (Novarel and Pregnyl) are indicated for:

  • Prepubertal cryptorchidism not due to anatomic obstruction
  • Selected cases of hypogonadotropic hypogonadism (hypogonadism secondary to a pituitary deficiency) in males.
  • Induction of ovulation and pregnancy in the anovulatory, infertile woman in whom the cause of anovulation is secondary and not due to primary ovarian failure, and who has been appropriately pretreated with human gonadotropins.
    
    

• Choriogonadotropin alfa (Ovidrel) is indicated for:

  • Induction of final follicular maturation and early luteinization in infertile women who have undergone pituitary desensitization and who have been appropriately pretreated with follicle stimulating hormones as part of an assisted reproductive technology (ART) program such as in vitro fertilization and embryo transfer.
  • Induction of ovulation (OI) and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to primary ovarian failure.

Compendial Uses

• Acute graft-versus-host disease (GVHD) (chorionic gonadotropin, Novarel, and Pregnyl only)
• Infertility, luteal phase support

Human chorionic gonadotropin (hCG), available for injection as Novarel (Ferring Pharmaceuticals, Inc.) and Pregnyl (Merck & Co, Inc.), is a polypeptide hormone produced by the human placenta. It acts primarily as a functional analog of pituitary luteinizing hormone (LH), with minor follicle-stimulating hormone (FSH) activity. Human chorionic gonadotropin stimulates gonadal steroidogenesis by binding to the LH / chorionic gonadotropin (CG) receptor: in males, it acts on Leydig cells to promote androgen production, which drives the development of secondary sex characteristics and can induce testicular descent in the absence of anatomical barriers. This effect is reversible upon discontinuation of hCG. In females, hCG stimulates the corpus luteum to produce progesterone, supporting the luteal phase and early pregnancy. During the menstrual cycle, LH and FSH together support follicular development, and the LH surge triggers ovulation—hCG can substitute for LH in this role, particularly in assisted reproduction protocols.

During pregnancy, hCG secreted by the placenta maintains the corpus luteum after LH secretion decreases, supporting continued secretion of estrogen and progesterone, and preventing menstruation.

Choriogonadotropin alfa (Ovidrel, EMD Serono, Inc.) is a recombinant form of human chorionic gonadotropin (hCG). It is essentially a lab-made version of hCG, which is a naturally occurring hormone produced during pregnancy. The physicochemical, immunological, and biological activities of recombinant hCG are comparable to those of placental and human pregnancy urine-derived hCG. 

Human chorionic gonadotropin is contraindicated in precocious puberty, prostatic carcinoma or other androgen-dependent neoplasm, prior allergic reaction to hCG. Human chorionic gonadotropin may cause fetal harm when administered to a pregnant woman. Combined hCG/PMS (pregnant mare's serum) therapy has been noted to induce high incidences of external congenital anomalies in the offspring of mice, in a dose-dependent manner. The potential extrapolation to humans has not been determined.

Per the label, hCG should be used in conjunction with human menopausal gonadotropins only by physicians experienced with infertility problems who are familiar with the criteria for patient selection, contraindications, warnings, precautions, and adverse reactions described in the package insert for menotropins. The principal serious adverse reactions during this use are: (i) ovarian hyperstimulation, a syndrome of sudden ovarian enlargement, ascites with or without pain, and/or pleural effusion; (ii) enlargement of preexisting ovarian cysts or rupture of ovarian cysts with resultant hemoperitoneum; (iii) multiple births, and (iv) arterial thromboembolism. Anaphylaxis has been reported with urinary-derived hCG products.

Induction of androgen secretion by hCG may induce precocious puberty in patients treated for cryptorchidism. Therapy should be discontinued if signs of precocious puberty occur. Since androgens may cause fluid retention, hCG should be used with caution in patients with cardiac or renal disease, epilepsy, migraine, or asthma.

Human chorionic gonadotropin can cross-react in the radioimmunoassay of gonadotropins, especially luteinizing hormone. Each individual laboratory should establish the degree of cross-reactivity with their gonadotropin assay. Physicians should make the laboratory aware of patients on hCG if gonadotropin levels are requested.

There have been sporadic reports of testicular tumors in otherwise healthy young men receiving hCG for secondary infertility. A causative relationship between hCG and tumor development in these men has not been established. Defects of forelimbs and of the central nervous system, as well as alterations in sex ratio, have been reported in mice on combined gonadotropin and hCG regimens. The dose of gonadotropin used was intended to induce superovulation. No mutagenic effect has been clearly established in humans.

Adverse reactions to hCG injection include headache, irritability, restlessness, depression, fatigue, edema, precocious puberty, gynecomastia, and pain at the site of injection. Hypersensitivity reactions both localized and systemic in nature, including erythema, urticaria, rash, angioedema, dyspnea and shortness of breath, have been reported. The relationship of these allergic-like events to the polypeptide hormone or the diluent containing benzyl alcohol is not clear. 

Human chorionic gonadotropin has not been demonstrated to be effective adjunctive therapy in the treatment of obesity. There is no substantial evidence that it increases weight loss beyond that resulting from caloric 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.

Safety and effectiveness in children below the age of 4 have not been established.

Endometrium Preparation for Frozen Embryo Transfer

Human chorionic gonadotropin is given to women to trigger ovulation once a naturally developing follicle is observed via ultrasound and hormone monitoring. This mimics the body's natural luteinizing hormone (LH) surge, helping to synchronize the timing of the endometrial lining (under the influence of the corpus luteum) with the embryo transfer. 

In the context of frozen embryo transfer (FET), hCG medications like Pregnyl and Novarel are typically timed when the lead follicle reaches about 18-20 mm in diameter (Baksh et al., 2021). However, hCG is not used to directly enhance endometrial development, but to ensure timely ovulation and synchronization of the luteal phase for embryo transfer. 

In a 2025 Cochrane review, Ghobara et al systematically evaluated 18 randomized controlled trials comparing various endometrial preparation regimens for frozen embryo transfer (FET) in ovulatory women. The review found no significant differences in live birth or ongoing pregnancy rates between natural cycles, modified natural cycles with hCG triggering, or hormone therapy (HRT) cycles, with or without GnRH-agonist suppression. All key outcomes (live birth, ongoing pregnancy, miscarriage, and multiple pregnancy) were statistically similar, with most evidence categorized as low or moderate certainty. 

There is no strong consensus or guideline recommending routine use of hCG for endometrial preparation in FET cycles without follicle stimulation, and the optimal protocol remains uncertain due to low-certainty evidence and variability in clinical practice. Thus, while hCG (Pregnyl or Novarel) may be used in specific artificial FET protocols, its use is not standard of care across all FET regimens (Ghobara et al., 2025; Zhang et al., 2023).

Male Infertility

In the American Urological Association (AUA) and American Society for Reproductive Medicine (ASRM) guideline on the diagnosis and treatment of infertility in men, Schlegel et al. (2021) recommended a comprehensive evaluation of male infertility that includes a reproductive history, physical examination, semen analysis, hormonal testing, and other diagnostic studies when indicated. The guideline recommends measurement of follicle-stimulating hormone and testosterone in infertile men with clinical features suggestive of hormonal abnormalities and notes that men with hypogonadotropic hypogonadism have deficient luteinizing hormone and follicle-stimulating hormone secretion, resulting in reduced testosterone production and impaired spermatogenesis. The authors state that spermatogenesis can often be initiated and pregnancies achieved in men with hypogonadotropic hypogonadism through treatment with exogenous gonadotropins, with human chorionic gonadotropin typically used initially and serum testosterone monitored for response; follicle-stimulating hormone or follicle-stimulating hormone analogues may subsequently be added to optimize sperm production. The guideline further notes that human chorionic gonadotropin, aromatase inhibitors, selective estrogen receptor modulators, or combinations of these therapies may be considered for infertile men with low serum testosterone, while testosterone monotherapy should be avoided in men seeking current or future fertility because it may suppress gonadotropin secretion and impair spermatogenesis.

In the AUA guideline on the evaluation and management of testosterone deficiency, Mulhall et al. (2018) stated that clinicians should use a total testosterone level below 300 ng/dL in support of the diagnosis of low testosterone and should make the diagnosis only after 2 early-morning total testosterone measurements obtained on separate occasions in the presence of symptoms and/or signs. The recommendations included consideration of testosterone testing in patients with unexplained anemia, bone density loss, diabetes, chemotherapy exposure, testicular radiation exposure, HIV/AIDS, chronic narcotic use, male infertility, pituitary dysfunction, or chronic corticosteroid use. Recommendations also include measurement of serum luteinizing hormone (LH) levels in patients with low testosterone and measurement of serum prolactin levels when LH levels were low or low/normal. Men interested in fertility preservation should undergo reproductive health evaluation before treatment, and exogenous testosterone therapy should not be prescribed to men actively trying to conceive. The authors provide a conditional recommendation (evidence level grade C) for use of aromatase inhibitors, human chorionic gonadotropin (hCG), selective estrogen receptor modulators, or a combination of these agents in men with testosterone deficiency who desired to maintain fertility; among these agents, only hCG has been FDA approved for use in males. The recommendations advised adjusting therapy to achieve total testosterone levels of 450-600 ng/dL, obtaining an initial follow-up testosterone level after treatment initiation, and measuring testosterone levels every 6-12 months during therapy.

Esteves et al. (2025) reviewed human chorionic gonadotropin (hCG)-based clinical treatments for infertile men with pre-testicular or testicular non-obstructive azoospermia and described the molecular properties, functions, preparations, pharmacology, patient stratification approaches, and therapeutic applications of hCG in spermatogenesis regulation. The narrative review examined evidence in males with hypogonadotropic hypogonadism and testicular non-obstructive azoospermia and summarized outcomes including restoration of spermatogenesis, sperm return to the ejaculate, sperm retrieval, pregnancy, and live birth outcomes. For pre-testicular non-obstructive azoospermia, the review summarized 50 studies including 2553 patients and reported that hCG-based therapy restored spermatogenesis to varying degrees in up to 100% of patients, with sperm returning to the ejaculate in an average of 69.5% of patients and successful natural or assisted conception occurring in an average of 25.6% of couples. The review also described a 2024 systematic review and meta-analysis including 5328 patients with hypogonadotropic hypogonadism that reported complete spermatogenesis in 86% of patients receiving combined therapy compared with 40% receiving hCG monotherapy. For testicular non-obstructive azoospermia, the review summarized 16 studies encompassing 4074 patients and reported that existing evidence indicated an overall positive impact of therapy on surgical sperm retrieval rates, particularly among patients with physiological gonadotropin levels. The review highlighted the APHRODITE criteria for patient stratification and emphasized assessment of hormonal profiles when considering hormonal treatment. The authors concluded that hCG treatment may alleviate infertility in azoospermic males, especially those with hypogonadotropic hypogonadism or testicular non-obstructive azoospermia accompanied by hypogonadism and normal physiological follicle-stimulating hormone levels, and stated that further research was required to define optimal candidates, treatment regimens, treatment duration, and the clinical role of recombinant luteinizing hormone.

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References