Clinical Research · Evidence reviews

Fertility and the epigenome, without the hype.

Two questions we are asked most about our Rx protocols. Does the Thymic Renewal (modified TRIIM), hormone or mitochondrial protocol help fertility? And do these protocols really change how DNA is read inside cells? Here is what the published evidence supports, where it stops, and how HelixCare clinicians plan around it.

Germ cells

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Article 01 · Fertility

Fertility on the protocols: what helps, what harms, and how we plan around it.

The short answer

None of our three protocols is a fertility treatment, and two of them contain medicines that can lower fertility or must be stopped before conception.

The parts with real fertility evidence are narrower: hCG protects sperm production in men on testosterone, and mitochondrial support for egg quality has promising but early data. With the right order and timing, most people can pursue these protocols and a pregnancy — just not always at the same time.

The Thymic Renewal protocol is modeled on the TRIIM pilot, which enrolled only nine men aged 51 to 65 and did not measure fertility at all¹. Our protocol page lists pregnancy and trying to conceive as reasons not to start it. The benefits below therefore come from the individual components, studied separately, and they are graded honestly.

Men

Testosterone lowers sperm production on its own

Injected testosterone signals the brain to stop releasing LH and FSH, the two hormones that tell the testes to make testosterone and sperm. Testosterone inside the testes then falls, even while blood levels look normal. The effect is strong enough that weekly testosterone injections were tested by the World Health Organization as a male contraceptive². Testosterone replacement alone is not a fertility therapy.

Why the male protocol includes hCG from day one

hCG acts like LH on the testes, keeping their own testosterone production and sperm-making machinery switched on. In a study of 26 men given 500 IU of hCG every other day alongside testosterone, none became azoospermic (no sperm in the ejaculate), and nine fathered a pregnancy during follow-up³. It was a retrospective study without a control group, but it is the reason hCG is part of the protocol rather than an add-on.

Anastrozole: only when estradiol is truly high

Some men convert too much testosterone into estradiol, which also suppresses LH and FSH. In infertile men with a low testosterone-to-estradiol ratio, aromatase inhibitors such as anastrozole raised that ratio and improved semen parameters in some groups⁴. In men with normal estradiol, pushing it lower brings no fertility benefit and harms bone, libido and mood, which is why our protocol uses it only after a sensitive estradiol test.

If conception is the goal now

A HelixCare clinician will usually pause testosterone and use hCG, sometimes with FSH, to restore or protect sperm production, confirmed with semen analyses. Sperm DNA also carries age-related methylation changes⁵, which Article 02 explains; no treatment has yet been shown to reverse them.

Growth hormone, DHEA and GLP-1 medicines in men. There is no good evidence that the Thymic Renewal protocol improves male fertility. Men planning a conception should tell their clinician before starting, and should have a baseline semen analysis.

Women

The female hormone protocol treats menopause, not infertility

Transdermal estradiol and micronized progesterone relieve menopause symptoms and protect bone⁶. After menopause they do not restore ovulation. In perimenopause, when cycles are irregular but eggs may still be released, hormone therapy is also not contraception, so pregnancy remains possible. Anyone still cycling who does not want to conceive needs a separate contraceptive plan.

GLP-1 medicines: plan the timing

In women whose ovulation is disrupted by insulin resistance or excess weight, lowering insulin and weight is a recognized route back to regular cycles. That is a clinical rationale rather than trial evidence for our specific protocol. Two label rules apply regardless:

Semaglutide should be stopped at least 2 months before a planned pregnancy, because it stays in the body for weeks⁷.
Tirzepatide can make oral contraceptive pills less reliable for 4 weeks after starting and after each dose increase, so a non-oral or backup method is needed during those windows⁸.

Growth hormone and DHEA in IVF

Both have been tried as add-ons for women who respond poorly to IVF stimulation, and neither has shown a reliable gain in live births:

Growth hormone slightly increased eggs retrieved and pregnancy rates in poor responders, but its effect on live birth is very uncertain⁹. Where it is used, it is given within a fertility clinic's stimulation cycle, not at TRIIM's year-long dosing.
DHEA likely makes little to no difference to live birth in poor responders, based on nine trials and 1,433 women¹⁰. We do not use it for fertility.

Egg and sperm quality: the mitochondrial link

An egg is one of the most mitochondria-dense cells in the body, and it relies on those mitochondria to divide its chromosomes correctly. As women age, oocyte mitochondria produce less energy, and errors in chromosome number become more common. This is where the mitochondrial protocol has its most interesting fertility rationale.

CoQ10, part of the protocol's supportive stack, restored oocyte mitochondrial function and fertility in aged mice. The same study found lower levels of CoQ-producing enzymes in older human oocytes¹¹. In a randomized trial in young women with low ovarian reserve, 200 mg three times daily for 60 days improved ovarian response and embryo quality¹².
SS-31 improved the quality of aged mouse oocytes: better chromosome alignment, fertilization and early embryo development, with less oxidative stress and DNA damage¹³. This is laboratory evidence only; SS-31 has not been studied for fertility or in pregnancy in humans.
MOTS-c has no published human fertility data.

Practical upshot. CoQ10 is the conception-compatible part of the mitochondrial protocol and can be started months before trying. SS-31 and MOTS-c are investigational and are stopped before conception attempts, with timing set by the prescriber.

At a glance

Fertility effect and pre-conception guidance for each protocol component
Component	Fertility effect	Before trying to conceive
Testosterone (men)Male protocol	Suppresses sperm production²	Pause or protect with hCG
hCG (men)Male protocol	Preserved sperm production alongside testosterone³	Continue; often used alone
Anastrozole (men)Male protocol	Helps only with a low testosterone-to-estradiol ratio⁴	Only if estradiol is high
Estradiol + progesteroneFemale protocol	Treats menopause; not fertility or contraception⁶	Discuss with a fertility specialist
Semaglutide / tirzepatideThymic Renewal protocol	May help cycles via weight and insulin; not a fertility drug	Semaglutide stopped ≥2 months before⁷
Growth hormoneThymic Renewal protocol	IVF live-birth benefit very uncertain⁹	Stop; protocol excludes conception
DHEAThymic Renewal protocol	Little to no live-birth difference¹⁰	Stop
CoQ10Mitochondrial stack	Better ovarian response and embryo quality in one RCT¹²	Can continue
SS-31 · MOTS-cMitochondrial protocol	SS-31 animal data only¹³; MOTS-c none	Stop; not studied in pregnancy

Status is shown as text and colour. Timing for every stop is set by the prescriber.

Planning a conception on a Binary Helix protocol

Step 1

Tell us first

If a pregnancy is possible in your plans, say so before any protocol starts, so components can be chosen and sequenced around it.

Step 2

Baseline fertility labs

Men: semen analysis, LH, FSH, testosterone. Women: AMH, antral follicle count, cycle day-3 FSH and estradiol. Results go into MyHelix.

Step 3

Washout on a calendar

Stop the medicines marked above on the prescriber's schedule, including at least 2 months off semaglutide, and use reliable contraception during tirzepatide dose windows.

Step 4

Refer and resume

Hand off to a reproductive endocrinologist or andrologist when needed. Protocols resume after conception attempts or pregnancy, when appropriate.

Article 02 · Epigenetics

How the protocols reach the epigenome, and what has actually been measured.

The short answer

None of these protocols edits your DNA sequence. What they can change is the chemical marking on DNA and its packaging proteins, which controls which genes cells read.

Two of the protocols' components have human trial data showing blood epigenetic clocks moving younger: the TRIIM regimen and semaglutide. For hormones and the mitochondrial peptides, the link is supported by mechanism and observational or animal studies, not yet by trials of our protocols.

What the epigenome is

Every cell carries the same DNA, but a liver cell and a neuron read different parts of it. The difference is written in the epigenome, a layer of chemical marks that do not change the genetic sequence:

DNA methylation: small methyl groups attached to cytosines, usually where a C is followed by a G (CpG sites). Methylation near a gene generally quiets it.
Histone modifications: DNA is wound around histone proteins. Acetyl marks loosen the winding so genes can be read; some methyl marks tighten it.
Chromatin structure: the overall folding that decides which regions are open to the cell's reading machinery.

With age, methylation drifts at predictable CpG sites. Epigenetic clocks such as GrimAge, PhenoAge and DunedinPACE read hundreds of these sites in a blood sample and estimate biological age or pace of aging. A younger clock reading is a biomarker change; it has not yet been shown to mean a longer life.

Four routes from a protocol to the DNA

Figure 1. Mitochondrial metabolites set epigenetic marks: the enzymes that write and erase them use TCA-cycle metabolites as fuel, co-factors or brakes¹⁴. Dashed arrow: inhibition. Simplified schematic, not to scale.

Metabolism writes the marks

The enzymes that add and remove epigenetic marks run on mitochondrial metabolites (Figure 1). Acetyl-CoA supplies histone acetylation; α-ketoglutarate is a required co-factor for TET enzymes that remove DNA methylation; and succinate and fumarate, which accumulate when mitochondria are stressed, inhibit those same enzymes¹⁴. This is the main biological reason a mitochondrial protocol, or better insulin control from a GLP-1 medicine, could shift the epigenome. It is a mechanism, not a measured result of our protocols.

Mitochondria signal the nucleus directly

MOTS-c is encoded in mitochondrial DNA. Under metabolic stress it moves into the nucleus and regulates nuclear genes, including antioxidant-response genes¹⁵. That is a change in which genes are read; a lasting change to methylation clocks has not been shown. In aged mouse oocytes, SS-31 shifted pathways for chromatin organization and histone modification, alongside less oxidative DNA damage¹³.

Hormones leave methylation signatures

Estrogen and androgen receptors bind DNA and recruit chromatin-modifying enzymes, so long-term hormone exposure leaves a record. In more than 3,100 women, earlier menopause and surgical removal of the ovaries were linked to faster epigenetic aging in blood, and women who had used menopausal hormone therapy had a younger epigenetic age in cheek cells¹⁶. For androgens, researchers have built an "androgen clock" that tracks long-term male hormone exposure; in animal experiments it stopped ticking after removal of the testes and started in females given androgens¹⁷.

Renewing cells changes the blood's average

Blood clocks read DNA from a mix of immune cells. When the thymus makes more new, naive T cells, the proportions of younger cell types rise, which can move a blood clock younger. This is how the TRIIM regimen's thymic effects and its clock results are thought to be linked¹, and why we measure immune cell types alongside every clock.

CpG sites

The sequence rendered here is rich in CG pairs, the sites where methylation clocks are read.

Evidence, by protocol

Epigenetic evidence for each Binary Helix protocol component
Protocol component	What was measured	Study type
TRIIM regimen (GH, DHEA, metformin)Thymic Renewal protocol	Four clocks averaged about 2.5 years younger than expected after 12 months; the GrimAge gain persisted 6 months after stopping¹	9 men · uncontrolled
SemaglutideReplaces metformin in our version	After 32 weeks: PCGrimAge 3.1 years lower, PhenoAge 4.9 years lower, DunedinPACE about 9% slower than placebo¹⁸	RCT · 45 vs 39 · post hoc
Menopausal hormone therapyFemale protocol	Lower epigenetic age in cheek cells among users¹⁶	Observational
TestosteroneMale protocol	Androgen exposure writes a measurable methylation signature¹⁷; no trial of testosterone therapy on aging clocks	Animal · mechanistic
MOTS-cMitochondrial protocol	Moves to the nucleus and regulates gene expression under stress¹⁵	Cell · animal
SS-31Mitochondrial protocol	Chromatin and histone-modification pathways shifted in aged oocytes¹³	Animal

Our modified Thymic Renewal protocol swaps metformin for a GLP-1 medicine. The combination has not been tested; the two rows above were separate studies in different people. The semaglutide trial was in adults with HIV-associated fat redistribution, and its epigenetic outcomes were analyzed after the trial rather than pre-specified¹⁸.

What we don't know yet

Whether a younger clock means a healthier, longer life. Clocks predict outcomes in large populations; reversing one has not been shown to change those outcomes.
Whether blood reflects other tissues. Most data come from blood, which also shifts with immune cell mix.
Whether changes last. In TRIIM, only the GrimAge gain clearly persisted after stopping¹.
Whether germ cells change. Age-related methylation changes in sperm are documented⁵, but no protocol has been shown to reverse them.

How we measure it. The Thymic Renewal protocol measures GrimAge, PhenoAge and DunedinPACE at baseline and 12 months, alongside immune cell types, with results stored in your MyHelix wallet. See our study pipeline

References

Published literature cited

Fahy GM, Brooke RT, Watson JP, et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell. 2019;18(6):e13028.
World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril. 1996;65(4):821–829.
Hsieh TC, Pastuszak AW, Hwang K, Lipshultz LI. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013;189(2):647–650.
Raman JD, Schlegel PN. Aromatase inhibitors for male infertility. J Urol. 2002;167(2 Pt 1):624–629.
Jenkins TG, Aston KI, Pflueger C, et al. Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility. PLoS Genet. 2014;10(7):e1004458.
The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767–794.
Novo Nordisk. WEGOVY (semaglutide) injection prescribing information: pregnancy and planned pregnancy.
Eli Lilly and Company. ZEPBOUND (tirzepatide) prescribing information: use with oral hormonal contraceptives.
Sood A, Mohiyiddeen G, Ahmad G, et al. Growth hormone for in vitro fertilisation (IVF). Cochrane Database Syst Rev. 2021;11(11):CD000099.
Naik S, Lepine S, Nagels HE, et al. Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction. Cochrane Database Syst Rev. 2024;6(6):CD009749.
Ben-Meir A, Burstein E, Borrego-Alvarez A, et al. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell. 2015;14(5):887–895.
Xu Y, Nisenblat V, Lu C, et al. Pretreatment with coenzyme Q10 improves ovarian response and embryo quality in low-prognosis young women with decreased ovarian reserve: a randomized controlled trial. Reprod Biol Endocrinol. 2018;16(1):29.
Xiong D, Zhang Y, Wei J, et al. SS-31 improves the quality of maternally aged oocytes by ameliorating mitochondrial function and metabolism. J Ovarian Res. 2026;19(1).
Martínez-Reyes I, Chandel NS. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun. 2020;11(1):102.
Kim KH, Son JM, Benayoun BA, Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018;28(3):516–524.
Levine ME, Lu AT, Chen BH, et al. Menopause accelerates biological aging. Proc Natl Acad Sci U S A. 2016;113(33):9327–9332.
Sugrue VJ, Prescott M, Glendining KA, et al. The androgen clock is an epigenetic predictor of long-term male hormone exposure. Proc Natl Acad Sci U S A. 2025;122(3):e2420087121.
Corley MJ, Dwaraka VB, Pang AP, et al. Semaglutide slows epigenetic aging in a randomized trial of HIV-associated lipohypertrophy. Nat Commun. 2026;17(1).

Educational review. These articles summarize published research for general information. They are not medical advice, fertility treatment or an offer of therapy. Several medicines discussed are prescribed off-label or are investigational (growth hormone for immune aging, SS-31 outside Barth syndrome, MOTS-c), and none of our protocols is approved or intended to treat infertility.

Epigenetic clock results describe biomarker changes in specific study populations and do not predict individual outcomes. Speak with a licensed clinician, and a reproductive specialist if you plan to conceive, before starting, stopping or changing any therapy.