First of all, make sure you are using LC/MS when testing for progesterone and pregnenolone if you want accurate numbers.
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Testosterone replacement therapy (TRT) lowers upstream hormones like progesterone and pregnenolone primarily due to its suppression of luteinizing hormone (LH), which is critical for stimulating the production of these hormones in the testes. Here’s a detailed breakdown:
### Mechanism of Hormone Suppression
1. **LH Shutdown**:
TRT introduces exogenous testosterone, which signals the pituitary gland to reduce LH production[1][4]. Since LH normally stimulates Leydig cells in the testes to produce testosterone and its precursors (including pregnenolone and progesterone), this suppression disrupts the entire steroidogenesis pathway[1][3][4].
2. **Impact on Upstream Hormones**:
- **Pregnenolone**: A precursor to all steroid hormones, its production in the testes declines without LH stimulation. While the adrenals can produce some pregnenolone, this is insufficient to maintain baseline levels[1][3].
- **Progesterone**: Conversion from pregnenolone is reduced due to decreased substrate availability. TRT may also impair 5α-reductase activity, an enzyme involved in converting progesterone to neuroactive metabolites like allopregnanolone[3][5].
3. **Adrenal Contribution**:
The adrenals continue producing small amounts of pregnenolone, but this does not compensate for the loss of testicular production[3].
### Clinical Evidence
- Studies show that TRT and anabolic steroids significantly reduce serum levels of pregnenolone, progesterone, and related metabolites[2][5]. For example, one study noted **~80–90% decreases in SHBG** and upstream hormones during steroid use[2].
- Measuring **17-hydroxyprogesterone (17OH-P)**, an upstream hormone, can help assess the effectiveness of therapies like hCG in restoring intratesticular testosterone (ITT). Levels below 215 ng/dL indicate impaired steroidogenesis due to LH suppression[4].
### Mitigation Strategies
- **hCG Co-Therapy**: Mimics LH to reactivate testicular hormone production, potentially normalizing upstream hormones like 17OH-P[4].
- **Pregnenolone/Progesterone Supplementation**: Some users report improved cognitive function and sleep with supplementation, though individual responses vary[1][5].
In summary, TRT-induced LH suppression disrupts the testicular production of upstream hormones, necessitating monitoring and potential adjunct therapies to address deficiencies[1][3][4][5].
Sources
[1] Anyone here taking progesterone?
Anyone here taking progesterone? - Excel Male TRT Forum
[2] Pregnenolone for Men: What We Need to Know
Pregnenolone for Men: What We Need to Know - Excel Male TRT Forum
[3] TRT Effect on 5 Alpha Reductase and Upstream Hormones
TRT Effect on 5 Alpha Reductase and Upstream Hormones- Cause of Low Mood and Anxiety? - Excel Male TRT Forum
[4] Best hCG Dose with TRT: 17-Hydroxyprogesterone Lab Test
Best hCG Dose with TRT: 17-Hydroxyprogesterone Lab Test - Excel Male TRT Forum
[5] Pregnenolone and Progesterone for Men
Pregnenolone and Progesterone for Men: Pharmacokinetics and Studies - Excel Male TRT Forum
[6] Pregnenolone 101: What You Need to Know About this ...
Pregnenolone 101: What You Need to Know About this Precursor Hormone - Excel Male TRT Forum
[7] Effect of TRT vs hCG/FSH on upstream hormone pathways.
Effect of TRT vs hCG/FSH on upstream hormone pathways. - Excel Male TRT Forum
[8] Comparison of Intratesticular Testosterone between Men ...
https://www.excelmale.com/attachments/2074wjmh_wjmh-41-390-pdf.31586/
[9] Pregnenolone makes high dose Testosterone tolerable
Pregnenolone makes high dose Testosterone tolerable - Page 9 - Excel Male TRT Forum
[10] TRT and immune system
TRT and immune system - Excel Male TRT Forum
[11] Progesterone in Men
Progesterone in Men - Excel Male TRT Forum
[12] TRT and Pregnenolone
TRT and Pregnenolone - Excel Male TRT Forum
[13] Low DHEA-S levels while on TRT
Low DHEA-S levels while on TRT - Excel Male TRT Forum
[14] Progesterone for sleep
Progesterone for sleep - Excel Male TRT Forum
[15] Help determining proper pregnenolone dosage and ...
Help determining proper pregnenolone dosage and frequency - Excel Male TRT Forum
[16] The Benefits of Estrogen in BodyBuilding
The Benefits of Estrogen in BodyBuilding - Excel Male TRT Forum
[17] Low progesterone? Frustrated. Thinking of pulling the plug ...
Low progesterone? Frustrated. Thinking of pulling the plug on TRT for good. - Excel Male TRT Forum
[18] Progesterone: the forgotten hormone in men?
https://www.excelmale.com/attachments/oettel-04-progesterone-men-am_1313008091-pdf.10531/
[19] Could the ratio of progesterone to estradiol affect water ...
Could the ratio of progesterone to estradiol affect water retention in men on TRT? - Page 2 - Excel Male TRT Forum
[20] Relationship between insulin resistance, estradiol ...
Relationship between insulin resistance, estradiol, aromatase, testosterone replacement, and water retention - Excel Male TRT Forum