CurrentCignaPolicy 1012

Injectable Fertility Medications (gonadotropins, hCG, GnRH agonists, menotropins)

Defines medical necessity criteria, authorization rules, and coding for injectable fertility medications for infertility treatment, fertility preservation, and males with hypogonadotropic hypogonadism under Cigna-administered plans.

Policy Summary

PayerCigna

PolicyInjectable Fertility Medications (gonadotropins, hCG, GnRH agonists, menotropins)

Policy CodePolicy 1012

Change TypeNo material change

Effective DateNov 15, 2024

Next Review Date

Key ActionObtain prior authorization and document that indication and required pre-treatment evaluations (exclude primary ovarian/testicular failure, confirm tubal patency when indicated, and monitor ovarian response with ultrasound and estradiol) are met.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

Up to 12 monthsinitial and reauthorization approval duration

Many plansinjectable fertility meds often excluded

5k–10k IUhCG trigger dose

Multiplecovered agents listed

Medical Necessity and Coverage Criteria

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Product-specific medical necessity criteria

Covered when the listed product-specific criteria are met

Chorionic Gonadotropin (Novarel, Pregnyl, chorionic gonadotropin): Considered medically necessary when ONE of the following are met: 1) Ovulation induction in females undergoing infertility treatment; 2) Ovulation induction in females undergoing fertility preservation; 3) Males with documented hypogonadotropic hypogonadism.

applies to Novarel, Pregnyl, chorionic gonadotropin entries

Follistim AQ (follitropin beta): Follistim AQ is considered medically necessary when BOTH of the following are met: 1) ONE of: a) Ovulation induction in females undergoing infertility treatment; b) Ovulation induction in females undergoing fertility preservation; c) Males with documented hypogonadotropic hypogonadism; AND 2) ONE of: a) Documentation of failure with Gonal-f; b) Patient has been started on a current cycle of therapy with Follistim AQ.

step requirement specific to Follistim AQ

Gonal-f (follitropin alfa): Gonal-f is considered medically necessary when ONE of the following are met: 1) Ovulation induction in females undergoing infertility treatment; 2) Ovulation induction in females undergoing fertility preservation; 3) Males with documented hypogonadotropic hypogonadism.

Leuprolide acetate / Lupron (all formulations): Leuprolide acetate (subcutaneous), Lupron injection, and Lupron Depot 3.75 mg are considered medically necessary when there is documentation that the medication is being used for treatment of female infertility.

applies to multiple formulations

Menopur (menotropins): Menopur is considered medically necessary when ONE of the following are met: 1) Ovulation induction in females undergoing infertility treatment; 2) Ovulation induction in females undergoing fertility preservation; 3) Males with documented hypogonadotropic hypogonadism.

Ovidrel (choriogonadotropin alfa): Ovidrel is considered medically necessary when ONE of the following are met: 1) Ovulation induction in females undergoing infertility treatment; 2) Ovulation induction in females undergoing fertility preservation.

Ovidrel criteria list only female indications

Medical necessity criteria for gonadotropin therapy

Covered when ALL of the following FDA-indicated conditions and pre-treatment evaluations are met:

Indication and evaluation: Indication matches FDA-labeled uses: induction of ovulation/pregnancy in anovulatory infertile women (functional, not primary ovarian failure), development of multiple follicles for ART, or induction of spermatogenesis in men with hypogonadotropic hypogonadism not due to primary testicular failure; and a complete gynecologic/endocrinologic or medical/endocrinologic evaluation has been performed.

Supported by product labeling

Exclude primary failure and pregnancy: Primary ovarian failure (in women) or primary testicular failure (in men) has been excluded; the possibility of pregnancy has been excluded prior to initiation.

Per product labeling

Partner/tubal evaluation when applicable: Tubal patency should be demonstrated for women being treated for infertility when indicated; the fertility status of the male partner should be evaluated prior to treatment initiation.

Per product labeling

FDA-recommended dosing and continuation criteria

Dosing and continuation criteria (clinical decision rules from FDA labeling):

Ovulation Induction dosing (Gonal-f RFF Redi-ject): Starting daily dose: 75 IU subcutaneously daily for 14 days in the first cycle. If indicated by ovarian response after initial 14 days, incrementally adjust up to 37.5 IU; additional incremental adjustments up to 37.5 IU may be made every 7 days. Maximum individualized daily dose 300 IU. In general, do not exceed 35 days of treatment. When pre-ovulatory conditions are reached, administer hCG; withhold hCG if ovarian monitoring suggests increased OHSS risk.see text

Starting doses <37.5 IU not studied; withhold hCG if OHSS risk increased

ART dosing for Gonal-f RFF: Begin on cycle day 2 or 3 with 150 IU daily (225 IU daily for women ≥35 with suppressed endogenous gonadotropins). Adjust dose after 5 days based on ultrasound and serum estradiol. Do not adjust more frequently than every 3–5 days or by more than 75–150 IU per adjustment. Continue until adequate follicular development, then administer hCG; withhold hCG if monitoring suggests increased OHSS risk. Typical ART duration generally should not exceed 10 days.see text

Per FDA ART guidance

Injectable fertility medications (including follitropins, hCG/choriogonadotropins, GnRH agonists such as leuprolide, and menotropins) are listed in this policy with product-specific medical necessity criteria. However, injectable fertility medications are specifically excluded under most benefit plans; providers must refer to the applicable benefit plan document to confirm whether coverage is available. When coverage is available, therapy is covered only when the product-specific criteria in this policy are met.

Treatment with gonadotropins or hCG is appropriate only for patients who meet FDA‑labeled indications and required pretreatment evaluations. The policy and product labeling require that primary ovarian failure in women and primary testicular failure in men be excluded before initiating therapy. Additionally, pregnancy must be excluded and, when indicated, tubal patency and male partner fertility should be demonstrated prior to treatment. Separately, hCG has not been demonstrated to be effective as adjunctive therapy for obesity and product information explicitly states it is not effective for weight‑loss adjunctive use.

Per FDA dosing guidance for ovulation induction, starting doses less than 37.5 International Units have not been studied and are not recommended. Initial regimens (for example, Gonal‑f RFF Redi‑ject) specify starting daily doses (e.g., 75 IU for first‑cycle ovulation induction) with incremental adjustments of up to 37.5 IU based on monitored ovarian response.

Any use of injectable fertility medications that does not meet the product‑specific medically necessary criteria listed in this policy is considered experimental, investigational, or unproven and is not covered.

Product labeling for chorionic gonadotropin (hCG; e.g., Novarel, Pregnyl) states that hCG has not been demonstrated to be effective as adjunctive therapy in the treatment of obesity. The labeling indicates there is no substantial evidence that hCG increases weight loss beyond caloric restriction or improves body fat distribution or hunger associated with calorie‑restricted diets.

FDA labeling provides limits on duration and maximum individualized dosing. For example, Gonal‑f RFF Redi‑ject guidance notes a maximum individualized daily dose of 300 International Units and states in general do not exceed 35 days of treatment. Treatment should be continued only until follicular growth and/or serum estradiol indicate adequate ovarian response, and hCG administration should be withheld if monitoring suggests increased OHSS risk.

Coding, Products, and Dosing Thresholds

Considered Medically Necessary when criteria metHCPCSCovered

J0725	Injection, chorionic gonadotropin, per 1,000 USP units
J1950	Injection, leuprolide acetate (for depot suspension), per 3.75 mg
J3355	Injection, urofollitropin, 75 IU
J3490	Unclassified drugs
J9217	Leuprolide acetate (for depot suspension), 7.5 mg
S0122	Injection, -menotropins, 75 IU
S0126	Injection, follitropin alfa, 75 IU
S0128	Injection, follitropin beta, 75 IU

Referenced gonadotropin products (FDA-labeled)mixed

Follistim AQ (follitropin beta)	FDA-labeled product name referenced
Gonal-f (follitropin alfa)	FDA-labeled product name referenced
Gonal-f RFF / Redi-ject (follitropin alfa)	FDA-labeled product name and delivery device referenced
Ovidrel (choriogonadotropin alfa)	hCG product for final follicular maturation and ovulation
Menopur (menotropins)	menotropin product for ART
Novarel / Pregnyl / chorionic gonadotropin	chorionic gonadotropin products referenced

Drug availability / product strengthsmixed

175 IU cartridge sizes etc.	Follistim AQ cartridge availability details (175, 350, 650, 975 IU cartridges) — product availability, not billing codes
300 IU; 450 IU; 900 IU	Gonal-f RFF Redi-ject available vial strengths (300 IU/0.5 mL, 450 IU/0.75 mL, 900 IU/1.5 mL)
10,000 USP	Chorionic gonadotropin vial availability (10,000 USP Units)
250 µg	Ovidrel prefilled syringe containing 250 µg choriogonadotropin alfa
75 IU FSH / 75 IU LH	Menopur vial composition (75 IU FSH and 75 IU LH activity)

Estradiol safety threshold for withholding hCG

Estradiol safety thresholdWithhold hCG if serum estradiol > 2,000 pg/mL (per product labeling).

When to consider withholdingWithhold hCG when ovarian monitoring suggests an increased risk of OHSS on the last day of therapy.

Source contextThreshold referenced in Gonal-f and Follistim labeling for completing follicular maturation and reducing OHSS risk.

hCG trigger dose for final oocyte maturation

Recommended hCG trigger doseAdminister hCG 5,000–10,000 IU to induce final oocyte maturation (depending on product).

TimingOocyte retrieval should be performed 34–36 hours after hCG administration for final maturation.

Withholding considerationDo not administer hCG if ovaries are abnormally enlarged or OHSS risk is increased on the last day of therapy.

Prior Authorization, Documentation, and Monitoring Requirements

Prior Authorization

Prior Authorization Required — Gonadotropin Therapy

Prior authorization is required for gonadotropin therapy when coverage is available and the request aligns with the policy's medical necessity criteria (e.g., ovulation induction, ART stimulation, or induction of spermatogenesis in men with hypogonadotropic hypogonadism). Requests should document that the indication matches FDA‑labeled uses or the specific coverage criteria listed in this policy.

Prior authorization must confirm the indication aligns with FDA‑labeled uses or applicable policy criteria.
Confirm that the requested product and dose are consistent with the individualized, stepwise dosing described in product labeling.

Prior Authorization

Prior Authorization — No Codes Listed

Some prior authorization sections in this policy do not list billing codes. Reviewers should rely on the medical necessity criteria, FDA dosing/availability details, and submitted clinical documentation to inform medical necessity determinations when codes are not listed.

No exhaustive code list provided in this section — use clinical criteria and prescribing details for review.
When codes are absent, ensure submitted documentation supports indication, dosing, and monitoring consistent with labeling.

Documentation Required

Pre‑treatment Evaluation Requirements

Prior to initiating gonadotropin therapy, a comprehensive pre‑treatment evaluation is required and must be documented. This evaluation is necessary to exclude primary ovarian/testicular failure, exclude pregnancy, demonstrate tubal patency (when applicable), and assess the fertility status of the male partner or perform semen analysis as indicated.

Exclude primary ovarian failure (women) or primary testicular failure (men).
Exclude pregnancy before treatment initiation.
Demonstrate tubal patency for women being treated outside of IVF programs when applicable.
Evaluate male partner fertility (semen analysis) where relevant.

Documentation Required

Required Clinical Documentation

Provide complete clinical documentation to support medical necessity for the specific product and indication. Documentation should include diagnostic evaluations, prior therapies and responses, and any product‑specific prerequisites described in the policy (for example, failure of an alternative product when required).

Complete gynecologic/endocrinologic or medical/endocrinologic evaluation as applicable.
Evidence excluding primary ovarian or testicular failure and excluding pregnancy.
Demonstration of tubal patency when indicated and evaluation of male partner fertility.
When the policy requires prior failure (e.g., Follistim AQ requires failure with Gonal‑f), include documentation of that prior therapy and outcome, or documentation that the member has already started a current cycle with the specified product.

Note

Clinical Sequencing Considerations

Clinical sequencing: gonadotropins are not first‑line therapy for certain anovulatory disorders (per ASRM guidance). Use gonadotropins after appropriate evaluation and when first‑line alternatives (where applicable) have been considered or have failed. For male hypogonadotropic hypogonadism, follow guideline‑based sequencing (hCG with or without FSH/HMG or pulsatile GnRH as appropriate).

ASRM: in anovulatory women, gonadotropins should not be first‑line for some conditions (e.g., PCOS) and should be started at low doses in gonadotropin‑naïve patients.
For male hypogonadism, follow EAU guidance regarding hCG ± FSH/HMG or pulsatile GnRH depending on etiology.

Step Therapy

Stepwise, Individualized Dosing and Monitoring

Dosing is stepwise and individualized. Start at the recommended initial dose for the product and adjust at specified intervals based on ovarian response (ultrasound and serum estradiol). Increase or decrease increments and maximum recommended doses differ by product; withhold or modify hCG administration when ovarian monitoring indicates increased risk of OHSS.

Start gonadotropin‑naïve patients at a low, product‑specific starting dose and individualize subsequent dosing.
Adjust doses at the intervals recommended in product labeling (e.g., weekly adjustments for Follistim AQ; after 5–7 days for Gonal‑f; every 3–7 days per product guidance).
Do not exceed product‑specific maximum daily doses (refer to FDA dosing sections).
Monitor ovarian response with ultrasound and serum estradiol to guide dose adjustments and timing of hCG; withhold hCG when monitoring suggests increased OHSS risk.

Terminology and Drug Class Definitions

Follitropins

DefinitionFollitropins are FSH preparations (recombinant or urinary) used to stimulate follicular development and spermatogenesis.

ProductionRecombinant follitropin alfa and beta are produced in CHO cells; urofollitropin is urine-derived from postmenopausal women.

ActivityThese preparations contain no LH activity and are used in combination with hCG to complete ovulation after follicular maturation.

GnRH agonist (Leuprolide)

DefinitionLeuprolide is a synthetic GnRH analog that initially increases, then with continued administration suppresses FSH and LH secretion.

Clinical effectContinuous use causes pituitary down-regulation and reduced sex steroid levels; normal function typically returns within ~3 months after stopping.

Use in ARTUsed adjunctively in ART protocols to prevent premature ovulation by suppressing the pituitary.

hCG / choriogonadotropin alfa

DefinitionhCG (chorionic gonadotropin or choriogonadotropin alfa) is a placenta-derived or recombinant hormone that mimics LH to trigger ovulation and stimulate androgen production in males.

FormsIncludes urine-derived chorionic gonadotropin (e.g., Novarel, Pregnyl) and recombinant choriogonadotropin alfa (Ovidrel).

FunctionSubstitutes for the mid-cycle LH surge to induce final follicular maturation and ovulation; stimulates Leydig cells to produce androgens in males.

Menotropins

DefinitionMenotropins are urine-derived preparations containing both FSH and LH activity used for ovulation induction and spermatogenesis.

CompositionBiologically standardized: one IU of FSH activity per one IU of LH activity; provides both pharmacologic effects.

Clinical useUsed in combination with hCG to induce ovulation after follicular maturation and to stimulate spermatogenesis in hypogonadotropic hypogonadism.

Ovulation induction / controlled ovarian stimulation

DefinitionUse of exogenous gonadotropins to induce follicular development and ovulation in anovulatory or ovulatory patients as part of ART cycles, with monitoring by ultrasound and serum estradiol.

ContextsApplied for ovulation induction in infertility treatment, fertility preservation, or controlled ovarian stimulation for IVF/ICSI.

MonitoringRequires individualized, stepwise dosing and regular ultrasound and estradiol monitoring to guide adjustments and trigger timing.

Induction of spermatogenesis

DefinitionInduction of spermatogenesis involves hCG administration to normalize testosterone followed by concomitant FSH (or menotropins) to stimulate sperm production in men with hypogonadotropic hypogonadism.

PretreatmentPretreatment with hCG alone is required to normalize serum testosterone (e.g., 1,500 IU twice weekly or 1,000–2,250 IU two to three times weekly depending on product) before adding FSH.

Duration and responseConcomitant therapy is continued for at least 3–4 months before improvement is expected; responses may take months and treatment may be continued up to ~12 months if needed.

Ovarian hyperstimulation syndrome (OHSS)

DefinitionOvarian hyperstimulation syndrome (OHSS) is an excessive ovarian response to stimulation where hCG administration should be withheld if monitoring suggests increased risk.

Relevance to hCGWithhold or do not administer hCG when ovarian monitoring indicates increased OHSS risk or when ovaries are abnormally enlarged on the last day of therapy.

Monitoring roleMonitor follicular growth and serum estradiol to assess OHSS risk and guide decisions to decrease, stop, or withhold gonadotropin/hCG dosing.

OpenPayer

Injectable Fertility Medications (gonadotropins, hCG, GnRH agonists, menotropins)

Medical Necessity and Coverage Criteria

Coding, Products, and Dosing Thresholds

Prior Authorization, Documentation, and Monitoring Requirements

Clinical Background and Scope

Terminology and Drug Class Definitions