Peptide Therapy Foundations: Hormonal & Sexual Health
Course Details
This course examines the peptides that act on sexual function and the hormonal axis that governs reproduction. It is written for clinicians who want to understand how these agents influence desire, arousal, and the upstream signaling of the reproductive system, and how the evidence behind each one should be read.
The lessons cover two mechanistic approaches. PT-141, a melanocortin receptor agonist, acts centrally on pathways tied to sexual desire and arousal. Kisspeptin-54 and Kisspeptin-10 sit further upstream, signaling through the KISS1 receptor to drive gonadotropin-releasing hormone and the hypothalamic-pituitary-gonadal axis. The two kisspeptin isoforms differ in size and signaling behavior, and the lessons keep them distinct.
Each lesson follows the same clinical lens: what the agent is, how it works, what the evidence shows, and what a practitioner weighs before applying it. Together they map the hormonal and sexual-health peptides as a group so you can reason about each one against the others.
SSRP FACULTY
William Seeds, MD
William Seeds, MD
William Seeds, MD
Before establishing the SSRP Institute, Dr. Seeds served as a board-certified orthopedic surgeon and sports medicine specialist for nearly three decades, including Chief of Surgery, Orthopedic Residency Site Director, and Director of The Ohio Bone & Joint Institute for University Hospitals.
His significant contributions to sports medicine have been recognized at the NFL Hall of Fame. He has consulted for athletes across all major sports leagues, including the NFL, NHL, MLB, NBA, and even the performers on “Dancing with the Stars.”
Through his research at the SSRP Institute, Dr. Seeds continues to explore the cellular pathways and mechanisms that positively impact disease and dysfunction in the body as well as optimize physical performance.
Kisspeptin-54
In-ProgressLesson Resources
Overview
Kisspeptin-54, also known as metastin, is the full-length, majority circulating isoform of kisspeptin and a master regulator of the hypothalamic-pituitary-gonadal (HPG) axis. It is a 54 amino acid peptide cleaved from a 145 amino acid precursor, the product of the KISS1 gene. This lesson covers its mechanisms, the human evidence, and where it currently sits in clinical investigation. Kisspeptin-54 has no FDA approval and remains investigational, with phase II work in in vitro fertilization (IVF) and psychosexual research.
The peptide carries a dual identity. It was first described in 1996 as a melanoma metastasis suppressor, then recognized in 2003 for its reproductive role. Both functions trace back to the same KISS1 isoforms, which share a decapeptide sequence required to activate the GPR54 (KISS1R) receptor.
Mechanism and signaling
Kisspeptin-54 binds GPR54 on gonadotropin-releasing hormone (GnRH) neurons in the arcuate and anteroventral periventricular nuclei of the hypothalamus. Binding triggers persistent depolarization of those neurons, driving GnRH release at the median eminence and downstream luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion from the anterior pituitary. That output drives gonadal steroidogenesis: testosterone in males, estradiol and progesterone in females. GnRH antagonist pretreatment blocks the effect, confirming a GnRH-dependent mechanism.
GPR54 is a G-protein coupled receptor signaling through Gαq/11, phospholipase C, IP3/DAG, and intracellular calcium mobilization, then PKC and the MAPK/ERK pathway. The same pathway downregulates NF-κB, which contributes to metastasis suppression through reduced matrix metalloproteinase activity.
Clinical evidence
In healthy males, IV infusion increased LH, FSH, and testosterone versus saline, with growth hormone, prolactin, and TSH unaffected and no changes in blood pressure or heart rate. In functional hypothalamic amenorrhea, kisspeptin-54 produced robust LH and FSH rises and increased LH pulsatility. IVF oocyte-maturation trials reported high maturation yields with no ovarian hyperstimulation, a contrast to HCG triggering. Functional MRI work showed modulation of limbic and arousal-related brain regions in psychosexual studies.
Compared with kisspeptin-10, kisspeptin-54 sustains LH release for one to four hours rather than minutes, reaches far higher peak plasma levels at equal molar doses, and crosses the blood-brain barrier.
Dosing and safety
Acute single dosing produces a predictable HPG response. Chronic twice-daily subcutaneous dosing over one to two weeks causes tachyphylaxis through GPR54 downregulation, so intermittent or pulsatile delivery is under investigation to preserve responsiveness. Across more than 500 subjects, no serious adverse events were reported; injection-site stinging occurred in up to half of subcutaneous injections.
Key clinical points
- Kisspeptin-54 is the full-length KISS1 isoform and a master regulator of the HPG axis via GPR54 on GnRH neurons.
- The GnRH-dependent mechanism drives LH and FSH release without affecting growth hormone, prolactin, or TSH.
- It crosses the blood-brain barrier and sustains LH release far longer than kisspeptin-10.
- Chronic frequent dosing can cause tachyphylaxis through receptor downregulation; pulsatile delivery is being studied.
- It remains investigational with no FDA approval; absolute contraindications include pregnancy and hormone-sensitive cancers.
Questions? Our Provider Care Team is here to help.
We'd love to help you determine the best next steps on your Cellular Medicine journey.
Continue your learning journey
VIEW ALLAging-Associated Decline of Phosphatidylcholine Synthesis is a Malleable Trigger of Natural Mitochondrial Aging
Dr. Seeds explores how age-related decline in phosphatidylcholine synthesis may contribute to mitochondrial aging and why that matters in Cellular Medicine. This discussion connects membrane integrity, mitochondrial function, methylation, and metabolic resilience, while highlighting how this pathway may be more modifiable than we once thought.
1. Managing shingles outbreaks in GLP-1 patient through peptides (0:40)
2. Peptide strategies in suspected ALS (15:56)
3. Improving durability in dementia treatment (25:08)
In this bonus episode from the MM15 Virtual Summit, Dr. Seeds addresses an important question around the use of GLP-1s for metabolic balancing in patients who do not need to lose weight. He shares his perspective on what may be considered microdosing, along with the clinical thought process he uses when determining appropriate dosing in these more nuanced cases.
Additional questions from the MM15 Virtual Summit can be found in our accompanying article here: [insert article link]
Access the full MM15 Course here: Mastermind 15 on Aesthetics
The Limits of Alternative Peptide Delivery
Dr. Seeds reviews oral, sublingual, and transdermal peptide delivery, and explains why subcutaneous injection remains the gold standard for most peptides. (Question Link)
A Deeper Look at the RAAS System
Dr. Seeds uses this Rabbit Holes episode to build on Journal Club Episode 87, revisiting the renin-angiotensin-aldosterone system and its broader role in cellular signaling. The discussion focuses on receptor balance, local tissue effects, and the mechanisms linking RAS disruption to inflammation, fibrosis, and mitochondrial stress.(Article Link)
The Renin–Angiotensin–Aldosterone System (RAAS): Beyond Cardiovascular Regulation
Dr. Seeds unpacks how RAS receptor balance drives inflammation, fibrosis, mitochondrial dysfunction, and tissue remodeling, far beyond its classical role in blood pressure regulation. (Article Link)
1. SSRI tapering resistance, anxiety during weaning (0:40)
2. Progressive multifocal dystonia (13:27)
3. Complex type 2 diabetes case in a lean, athletic patient (28:32)