Are estrogen and progesterone (estrogen and progesterone) levels lower during embryo transfer in in vitro fertilization (IVF) due to exogenous supplementation?

Estrogen and Progesterone Levels During Embryo Transfer with Exogenous Supplementation

No, estrogen and progesterone levels are not inherently lower during embryo transfer due to exogenous supplementation—in fact, they are typically maintained at supraphysiological levels in stimulated IVF cycles, while in hormone replacement frozen embryo transfer (HRT-FET) cycles, exogenous hormones replace endogenous production to achieve target therapeutic levels. 1

Understanding Hormone Dynamics in Different IVF Protocols

Fresh Embryo Transfer Cycles (Stimulated Cycles)

In fresh IVF cycles using GnRH agonist/gonadotropin protocols for ovarian stimulation:

• Estradiol levels are supraphysiological throughout both the follicular and luteal phases, significantly exceeding natural cycle levels 2
• Peak follicular estradiol levels correlate positively with midluteal progesterone and estradiol levels in both successful and unsuccessful cycles 2
• These elevated hormone levels persist despite exogenous hCG luteal support, as multiple corpora lutea continue producing endogenous steroids 2
• The concern is not that levels are too low, but rather that excessively high estrogen levels may negatively impact implantation by narrowing the window of uterine receptivity 3

Frozen Embryo Transfer with Hormone Replacement (HRT-FET)

In programmed FET cycles with exogenous estrogen and progesterone supplementation:

• Endogenous hormone production is suppressed by the exogenous supplementation, but total circulating levels are maintained at therapeutic targets 4, 5
• Late follicular phase serum estradiol levels in HRT-FET cycles do not predict implantation or pregnancy outcomes, suggesting adequate replacement is achieved 4
• The key is achieving appropriate exogenous hormone levels, not the source (endogenous vs. exogenous) 6
• When synthetic progestogens are used, endogenous progesterone can still be measured and reflects placental activity starting at 5-6 weeks of pregnancy 5

Critical Hormone Level Considerations

Progesterone Thresholds

Progesterone levels require careful monitoring as both deficiency and premature elevation affect outcomes:

• Progesterone levels >2.86 nmol/L (0.9 ng/mL) on the day of hCG administration are associated with zero clinical pregnancies in fresh cycles 7
• Even modest elevations >1.27 nmol/L (0.4 ng/mL) significantly reduce pregnancy rates compared to lower levels 7
• This premature progesterone rise likely affects endometrial receptivity rather than oocyte quality, as frozen embryo transfers from affected cycles can still result in pregnancy 7

Estrogen's Role in Uterine Receptivity

Estrogen levels within a narrow physiological range are critical for optimal implantation:

• The window of uterine receptivity remains open longer at lower estrogen levels but rapidly closes at higher levels 3
• Higher estrogen concentrations cause uterine refractoriness with aberrant expression of implantation-related genes 3
• In HRT-FET protocols, standard dosing (e.g., Progynova 6mg daily) for 12-14 days achieves adequate endometrial preparation without excessive levels 6

Clinical Algorithm for Hormone Management

For Fresh IVF Cycles:

1. Monitor progesterone on day of hCG trigger 7

   • If P4 <1.27 nmol/L: Proceed with fresh transfer (optimal pregnancy rates)
   • If P4 1.27-2.86 nmol/L: Consider fresh transfer (reduced but possible pregnancy)
   • If P4 >2.86 nmol/L: Freeze all embryos and perform FET in subsequent cycle 7

2. Track estradiol levels but recognize supraphysiological levels are expected and correlate with ovarian response 2

For HRT-FET Cycles:

1. Estrogen priming phase: Continue estradiol valerate 6mg daily for 12-14 days minimum 6

2. Endometrial assessment: Confirm thickness ≥7-8mm with trilaminar pattern before progesterone initiation 6

3. Progesterone supplementation: Initiate 800mg vaginal daily once adequate endometrial development confirmed 6

4. Transfer timing: Calculate precisely from first progesterone dose (117-120 hours for blastocyst transfer) 6

Common Pitfalls to Avoid

• Do not assume exogenous supplementation means inadequate levels—the goal is therapeutic replacement, not replication of natural cycle levels 4
• Avoid measuring only total hormone levels in fresh cycles without considering the timing and source (multiple corpora lutea vs. single corpus luteum) 2
• Do not start progesterone on fixed cycle days in HRT-FET without confirming adequate endometrial preparation 6
• Recognize that in synthetic progestogen protocols, endogenous progesterone measurement remains valuable for assessing early placental function 5

The evidence clearly demonstrates that exogenous supplementation in IVF does not result in lower hormone levels—rather, it either maintains supraphysiological levels (fresh cycles) or achieves adequate therapeutic replacement (FET cycles) to support implantation and early pregnancy.