Pregnenolone & IVF: What You Need to Know

randomized-controlled-trial PMID: 38037188

Quick Summary: Research shows that different fertility drugs affect how your body uses pregnenolone, a building block for hormones. One drug, hp-HMG, may help keep progesterone levels lower during IVF, which could improve success.

What The Research Found

This study looked at how two different fertility drugs impact hormone levels during IVF. They found that:

hp-HMG (a drug containing FSH and LH) led to lower progesterone levels compared to r-FSH (a drug containing only FSH).

This difference is because hp-HMG changes how your body uses pregnenolone. It pushes the body to make more androstenedione, which is a precursor to other hormones, instead of progesterone.

Both drugs resulted in similar numbers of eggs retrieved.

Study Details

Who was studied: 112 healthy women aged 18-35 who were donating eggs for IVF.

How long: The study followed the women through their IVF cycle, about 8-10 days.

What they took: Women received either:

hp-HMG (225 IU daily)
r-FSH (225 IU daily)

What This Means For You

If you're undergoing IVF, this research suggests:

The type of fertility drug used might affect your hormone levels.

Lower progesterone levels during the egg retrieval phase may lead to better outcomes.

Talk to your doctor about the best fertility drug for your specific needs and medical history.

Study Limitations

Specific Group: The study only included young, healthy women donating eggs. The results may not apply to all women undergoing IVF, especially those with fertility issues or other health conditions.

Measurement Issues: Hormone levels were measured using a specific method that can have some variability.

Funding: The study was funded by a company that makes one of the drugs.

Key Findings

The study demonstrated that ovarian stimulation with highly purified human menopausal gonadotropin (hp-HMG) versus recombinant FSH (r-FSH) led to distinct follicular steroidogenesis pathways. hp-HMG preferentially enhanced the Δ4 pathway, converting pregnenolone to androstenedione, resulting in lower serum progesterone levels on the day of triggering (0.46 ± 0.27 ng/ml vs. 0.68 ± 0.50 ng/ml with r-FSH; P = 0.010). Conversely, r-FSH promoted pregnenolone-to-progesterone conversion. The pregnenolone:progesterone ratio increased significantly in the r-FSH group (P = 0.019), while the pregnenolone:androstenedione ratio was higher in hp-HMG (P = 0.012). Both groups had comparable ovarian response (mean oocytes: 17.5 vs. 16.5; P = 0.49), indicating the steroidogenic differences were independent of follicular development.

Study Design

This was a randomized controlled trial (RCT) conducted at a university-affiliated infertility clinic. A total of 112 oocyte donors (aged 18–35 years, normal BMI, AMH 10–30 pMol/l) underwent ovarian stimulation with GnRH antagonists and either r-FSH (225 IU/day) or hp-HMG (225 IU/day). Hormone levels (progesterone, pregnenolone, androstenedione, etc.) were measured in serum and follicular fluid on Days 1, 4, 6, 8, and triggering day. Polynomic extrapolation compared total hormone exposure across the follicular phase.

Dosage & Administration

Both groups received 225 IU/day of their assigned treatment subcutaneously. The hp-HMG group received Menopur® (contains both FSH and LH activity), while the r-FSH group received Gonal-F® (pure FSH). Stimulation duration was not explicitly stated but spanned 8–10 days on average, aligned with standard IVF protocols.

Results & Efficacy

Progesterone: Significantly lower in hp-HMG at triggering (P = 0.010) and Days 6/8.
Androstenedione: Higher in hp-HMG on triggering day (3.0 ± 1.4 ng/ml vs. 2.4 ± 1.1 ng/ml; P = 0.015) and Day 8.
Steroid ratios: Pregnenolone:progesterone ratio increased in r-FSH (P = 0.019); pregnenolone:androstenedione ratio was higher in hp-HMG (P = 0.012).
Follicular fluid: Estradiol (E2), LH, and androgens were elevated in hp-HMG, but progesterone levels were similar between groups.

Limitations

Population specificity: Participants were young, fertile oocyte donors with normal BMI and ovarian reserve; results may not generalize to infertile patients or those with hormonal imbalances.
Assay variability: Hormone measurements used immunoassays, which have inherent intra-assay variability.
Funding bias: Supported by Roche Diagnostics (manufacturer of r-FSH); potential conflicts of interest noted for several authors.
Mechanistic gaps: Pathway differences were inferred from hormone ratios without direct enzymatic or genetic analysis.

Clinical Relevance

For IVF protocols using fresh embryo transfer, hp-HMG may mitigate progesterone elevation during the follicular phase, which is linked to reduced clinical success. This effect appears independent of ovarian response, suggesting hp-HMG could benefit patients at risk of premature luteinization. However, the study’s focus on oocyte donors limits applicability to broader populations. Clinicians should consider these findings when selecting gonadotropins for stimulation, particularly in cases where progesterone control is critical.

Implications for Supplement Users

This study does not directly assess Pregnenolone supplementation but highlights its role as a steroidogenic precursor in ovarian hormone regulation. For individuals using Pregnenolone supplements, the findings underscore its metabolic flexibility and dependence on enzymatic pathways influenced by external factors (e.g., gonadotropins). However, no conclusions about Pregnenolone supplementation efficacy for progesterone modulation can be drawn from this IVF-focused trial.

Trial Registration: NCT02738580 (registered February 2016).