Fertility (Male & Female)

Infertility is usually defined as no pregnancy after 12 months of regular unprotected sex, or after 6 months when the woman is 35 or older. The WHO estimates it affects about 1 in 6 adults worldwide at some point. It has many causes: ovulation disorders (PCOS is the most common), blocked or damaged fallopian tubes, endometriosis, declining egg number and quality with age, uterine problems, and male factors such as low sperm count or poor sperm function. A male factor contributes in roughly half of couples. In a substantial minority, often quoted as 15–30%, a full standard workup finds no cause at all. This is 'unexplained infertility'.

Reproduction is run by peptide and protein hormones: GnRH from the hypothalamus, LH and FSH from the pituitary, hCG from the placenta, and kisspeptin upstream of them all. As a result, peptide drugs are the backbone of reproductive medicine. hCG, hMG (and recombinant FSH) and the GnRH agonists and antagonists are standard, regulator-approved tools in IVF and in treating men and women whose brain does not send the signal to their gonads. Of all the conditions on this site, this one has some of the strongest peptide evidence. But the evidence is narrow. These drugs either replace a missing hormonal signal or let a specialist control a stimulated cycle under close monitoring. They do not make a normally working reproductive system 'more fertile'.

This page explains which peptides have real evidence for which diagnoses in men and women, and the common question of hCG for men on testosterone. It also explains why the 'fertility peptide stacks' sold online are a different matter entirely. Doses here are deliberately left to reproductive endocrinologists and andrologists. This page is informational, not medical advice.

How peptides target fertility (male & female)

The reproductive axis is a chain of peptide signals. Kisspeptin neurons in the hypothalamus drive pulses of GnRH. GnRH tells the pituitary to release LH and FSH. In women, FSH grows ovarian follicles and an LH surge triggers final egg maturation and ovulation. In men, LH drives testosterone production in the testes and FSH (together with that local testosterone) drives sperm production. Each fertility peptide acts at one point in this chain.

hCG acts on the same receptor as LH but lasts much longer. In IVF it is the classic 'trigger shot' that completes egg maturation before retrieval. In men it stands in for LH, restarting testosterone production inside the testes. hMG (menotropins) supplies both FSH and LH activity and is used to grow multiple follicles in IVF and, together with hCG, to start sperm production in men whose pituitary does not make gonadotropins.

GnRH (gonadorelin is the synthetic version) behaves in opposite ways depending on how it is given. Pulses every 60–120 minutes from a pump mimic the natural rhythm and restart the axis. This is the treatment for women with hypothalamic amenorrhea and for men with hypothalamic hypogonadism such as Kallmann syndrome. Continuous exposure to a long-acting GnRH agonist (leuprolide, triptorelin) does the reverse: after a brief flare it shuts the pituitary down. IVF uses both effects. Agonists or antagonists prevent premature ovulation during stimulation, and a single agonist dose can trigger egg maturation with a much lower risk of ovarian hyperstimulation syndrome (OHSS) than hCG. The GnRH antagonists used in IVF (cetrorelix and ganirelix) are peptides too, though this site does not yet have pages for them.

Kisspeptin sits at the top of the chain. A single injection makes the woman's own pituitary release a shorter, more physiological LH surge than an hCG trigger provides, which is why Imperial College London has studied it as a gentler IVF trigger for women at high risk of OHSS.

hCG for men on testosterone. Testosterone replacement therapy (TRT) suppresses LH and FSH, which removes the signal the testes need to make sperm. Many men on TRT develop very low sperm counts or none at all. Low-dose hCG given alongside TRT replaces the missing LH signal, keeps testosterone high inside the testes, and aims to preserve sperm production and testicular size. For men with low testosterone who want fertility, the oral non-peptide alternatives are clomiphene or enclomiphene (selective estrogen receptor modulators) and aromatase inhibitors, which raise the body's own LH and FSH instead of replacing testosterone.

What the evidence shows

Men with hypogonadotropic hypogonadism: strong evidence. When the problem is a missing pituitary or hypothalamic signal (congenital, as in Kallmann syndrome, or acquired from pituitary disease), gonadotropin therapy works. A meta-analysis (Rastrelli et al., Andrology 2014) pooled 44 gonadotropin studies and 16 GnRH studies. Both approaches produced sperm in about 75% of previously azoospermic men, with a mean final sperm concentration of about 6 million/mL. That is low, but often enough for natural conception or IVF with ICSI. Results were better when the condition started after puberty, and earlier testosterone treatment did not worsen them. The usual sequence is hCG first, with FSH (recombinant or as hMG) added if sperm do not appear.

Men on TRT: reasonable but limited evidence. The AUA/ASRM male infertility guideline says clinicians should not prescribe testosterone to men interested in current or future fertility. The main hCG-plus-TRT study (Hsieh et al., J Urol 2013) was a retrospective series of 26 men given 500 IU intramuscular hCG every other day alongside testosterone. Semen parameters held steady, no man became azoospermic, and 9 contributed to a pregnancy. It is small and uncontrolled. The same guideline allows hCG, SERMs or aromatase inhibitors for infertile men with low testosterone (a conditional recommendation, grade C evidence). For men with idiopathic infertility, it allows FSH to be considered to improve sperm concentration and pregnancy rates (conditional, grade B), a modest effect from a prescribed, monitored treatment. None of these help primary testicular failure, where the testes cannot respond (high FSH, often azoospermic). Those men need surgical sperm retrieval with ICSI or donor sperm.

IVF and ovarian stimulation: strong evidence and standard practice. Recombinant FSH and hMG are equally recommended for stimulation in ESHRE's 2025 ovarian stimulation guideline. The guideline strongly recommends the GnRH antagonist protocol over GnRH agonist protocols for the general IVF population, because the two are similarly effective and the antagonist is safer. It also strongly recommends a GnRH agonist trigger with all embryos frozen for women at risk of OHSS. Leuprolide is used this way off-label in the US; triptorelin is approved for IVF in many other countries.

Kisspeptin as an IVF trigger: promising, still investigational. In the first trial (Jayasena et al., JCI 2014), a single kisspeptin-54 injection matured eggs in 53 women having IVF. 92% went on to embryo transfer, and 23% had a clinical pregnancy. In a phase 2 trial in 60 women at high risk of OHSS (Abbara et al., JCEM 2015), eggs matured in 95%, the live birth rate per transfer was 45%, and no woman developed moderate or severe OHSS. These were small dose-finding studies without an hCG comparison group. Kisspeptin is not approved anywhere for this use, and ESHRE's 2025 guideline does not list it among recommended triggers. The GnRH agonist trigger already addresses OHSS in standard practice.

Hypothalamic amenorrhea: established. The Endocrine Society's 2017 guideline on functional hypothalamic amenorrhea recommends pulsatile GnRH as first-line ovulation induction once the workup is complete, alongside correcting the underlying energy deficit. Gonadotropins are the alternative where GnRH pumps are unavailable, as they are in the US, where no pulsatile gonadorelin product is currently marketed. Twice-weekly kisspeptin in hypothalamic amenorrhea has been studied only in research settings.

Unexplained infertility: no targeted peptide. ASRM's 2020 guideline calls treatment of unexplained infertility 'by necessity empiric'. For most couples the best start is 3–4 cycles of ovarian stimulation with oral drugs plus intrauterine insemination, then IVF. Gonadotropins and GnRH drugs appear inside IVF, but as tools to produce and time eggs, not as treatments for a hidden cause. No trial shows that adding kisspeptin, gonadorelin, hCG or any other peptide improves fertility in someone whose reproductive hormones are already normal.

What to expect

Men with hypogonadotropic hypogonadism. Testosterone usually normalizes within weeks to a few months of starting hCG. Sperm production takes far longer: typically 6–12 months, sometimes up to 2 years, especially when the condition began before puberty. Semen analyses track progress, and banking sperm once it appears is common. Final counts are often below the 'normal' range yet still adequate for conception, with or without IVF/ICSI.

Men on TRT. Adding hCG preserved semen parameters in most men in published series, but it is not guaranteed. A semen analysis before starting and periodically afterward is the only way to know. Men who are already azoospermic on TRT are usually advised to stop testosterone and switch to an hCG-based regimen (sometimes with FSH or a SERM). Recovery commonly takes 6–12 months and occasionally longer. hCG raises estradiol along with testosterone, so breast tenderness or gynecomastia can occur, and estradiol is monitored.

Women having IVF. Ovarian stimulation means daily injections, usually for about 8–14 days, with ultrasound and estradiol checks to adjust the dose. The trigger (hCG, a GnRH agonist or a combination) is timed 34–36 hours before egg retrieval. After an hCG trigger, home pregnancy tests can read falsely positive for up to about two weeks. Symptoms of OHSS (marked bloating, rapid weight gain, shortness of breath, reduced urination) need prompt medical attention.

Women with hypothalamic amenorrhea. Pulsatile GnRH restores ovulation in most cycles and usually produces a single follicle, so twins and triplets are much less likely than with gonadotropins. In the US, gonadotropins with close monitoring are the practical alternative.

All doses, protocols and durations should be set and supervised by a reproductive endocrinologist or andrologist. Figures from studies are for context, not instructions.

What NOT to expect from any peptide: better egg quality, a reversal of age-related fertility decline, a fix for blocked tubes or primary testicular failure, or a meaningful benefit in people whose reproductive hormones are already normal.

Frequently asked questions

References

• Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilizationClinical Trial

  Jayasena, Abbara, Dhillo et al. (Imperial College London), JCI 2014. The first human study of kisspeptin as an IVF trigger. A single subcutaneous kisspeptin-54 injection matured eggs in 53 women, 92% reached embryo transfer and 23% had a clinical pregnancy, establishing proof of concept for a natural-LH-surge trigger.

• Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) TherapyRandomized Controlled Trial
• Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapyRetrospective Study

  Hsieh et al., J Urol 2013. 26 hypogonadal men on TRT plus 500 IU intramuscular hCG every other day had stable semen parameters over follow-up, none became azoospermic and 9 contributed to a pregnancy. This small, uncontrolled study is the main basis for the common hCG-with-TRT protocol.

• Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a meta-analytic studyMeta-Analysis
• Diagnosis and treatment of infertility in men: AUA/ASRM guideline part IIGuideline
• ESHRE guideline: ovarian stimulation for IVF/ICSI: an update in 2025Guideline
• Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice GuidelineGuideline
• Evidence-based treatments for couples with unexplained infertility: a guidelineGuideline

  ASRM Practice Committee, Fertil Steril 2020. Treatment of unexplained infertility is necessarily empiric. For most couples the best initial therapy is 3–4 cycles of ovarian stimulation with oral medication plus intrauterine insemination, followed by IVF. No hormone or peptide 'fix' exists because no underlying cause has been identified.

Part of these goals

Related conditions

• Low Testosterone
• PCOS