The Doses

§ I · How to read this chapter

How to read this chapter

This chapter catalogues the dose figures that have appeared in the peer-reviewed sermorelin literature and on the historic FDA-approved Geref label. It is not a dosing guide. The site does not recommend any dose for any human, does not provide medical advice, does not prescribe, and does not dispense any product. The figures below are presented because they form part of the historical and research record that any reader of the sermorelin literature will encounter; they are not extracted from that record as guidance.

§ II · The historic Geref label (1997-2008)

The historic Geref label (1997-2008)

The Geref new drug application (NDA 020443) was approved by the FDA in 1997 for two indications ^[1][18]. The therapeutic indication was pediatric idiopathic growth-hormone deficiency. The labeled dose was thirty micrograms per kilogram of subcutaneous sermorelin acetate, administered once daily at bedtime. The pivotal study reported mean height velocity rising from 4.1 centimeters per year at baseline to 8.0 at six months in this dose ^[1].

The diagnostic indication was provocative pituitary stimulation testing. The labeled diagnostic dose was one microgram per kilogram of intravenous sermorelin as a single bolus, with serum growth hormone sampled at zero, fifteen, thirty, forty-five, and sixty minutes. A 1999 review summarized the diagnostic test as specific for GHD with a low false-positive rate, with the caveat that hypothalamic-origin GHD cannot be ruled out because sermorelin acts directly on the pituitary, bypassing hypothalamic GHRH neurons ^[19].

The manufacturer voluntarily discontinued Geref in 2008. The FDA's March 4, 2013 Federal Register determination (78 FR 14114) affirmed that the withdrawal was not for reasons of safety or effectiveness ^[18]. No FDA-approved finished sermorelin product is currently on the U.S. market.

§ III · Adult research doses in the published literature

Adult research doses in the published literature

The adult-research dose figures vary across trials and were not standardized — no FDA-approved adult sermorelin dose exists.

In the Corpas 1992 study at the National Institute on Aging, healthy older men received either 0.5 milligrams or 1.0 milligrams of subcutaneous GHRH(1-29) twice daily for fourteen days ^[2]. Both arms restored mean twenty-four-hour GH and IGF-1 to values comparable to healthy young controls.

In the Khorram 1997 sixteen-week trial of healthy older adults, the dose was ten micrograms per kilogram of subcutaneous [Nle27]GHRH(1-29) administered nightly at twenty-one hundred hours, with a four-week placebo lead-in ^[3]. This trial produced the 1.26-kilogram lean-mass gain in men, the insulin-sensitivity improvement in men, and the dermal skin-thickness increase in both sexes.

The Vitiello 2006 cognitive trial used daily GHRH(1-29) for six months in healthy older adults ^[16]. The Baker 2012 cognitive trial used one milligram of subcutaneous tesamorelin (a stabilized GHRH-class analog of the same mechanism) nightly for twenty weeks in older adults aged fifty-five to eighty-seven — both healthy and with mild cognitive impairment — and reported the executive-function signal ^[4]. The tesamorelin HIV-lipodystrophy registration trial used two milligrams of subcutaneous tesamorelin daily for twenty-six weeks ^[15].

§ IV · Half-life and the engineering of nightly bedtime dosing

Half-life and the engineering of nightly bedtime dosing

Plasma half-life of sermorelin in adults is approximately eleven to twelve minutes following either intravenous or subcutaneous administration, with plasma clearance of approximately 2.4 to 2.8 liters per minute ^[6]. This is short by pharmacologic standards, and it is short by design. The intended pharmacodynamic effect of a sermorelin dose is one discrete physiologic GH pulse, not sustained receptor occupancy.

The rapid clearance is driven principally by dipeptidyl peptidase IV cleavage of the N-terminal Tyr-Ala dipeptide of sermorelin ^[6]. Bedtime dosing is the conventional schedule across the pediatric and adult research literature because endogenous GH secretion is sleep-coupled — the largest physiologic GH pulses occur during slow-wave sleep, in the deep stages of NREM that consolidate during the first third of the night ^[4]. A sermorelin dose timed to bedtime is engineered to reinforce a pulse the body would have fired anyway.

The DPP-IV-resistant GHRH analogs — Modified GRF (1-29), CJC-1295 without DAC — substitute D-alanine at position two to block DPP-IV cleavage and extend the functional half-life to approximately thirty minutes ^[14]. These analogs preserve the same receptor mechanism but extend the signaling window. Sermorelin is preferred in research protocols where strict physiologic pulsatility is the design intent.

§ V · Routes studied

Routes studied

The route most consistently studied across pediatric and adult research is subcutaneous injection ^[1][2][3][4]. Intravenous administration is used in the diagnostic stimulation-test protocol only ^[19]. Sublingual and oral troche formulations exist in some compounded research preparations but the bioavailability data is limited and the published research base is sparse compared with subcutaneous administration. The pediatric and adult-research literature is overwhelmingly a subcutaneous literature.

§ VI · IGF-1 monitoring — the biomarker the literature turns on

IGF-1 monitoring — the biomarker the literature turns on

Serum insulin-like growth factor 1 is the standard blood biomarker used to monitor the GH/IGF-1 axis response to GHRH-class compounds in adult research and clinical practice ^[12]. IGF-1 has a long half-life relative to GH itself and integrates the pulsatile GH signal over hours to days, which makes it a more practical biomarker for outpatient and telemedicine monitoring than direct GH pulse sampling.

The additional labs commonly tracked in adult-research and telehealth practice include IGFBP-3 (the principal IGF-1 binding protein), fasting glucose, hemoglobin A1c, fasting insulin and HOMA-IR, the comprehensive lipid panel, thyroid-stimulating hormone with free T4, and a baseline cancer-screening history ^[12]. Adult research protocols typically check IGF-1 at four to eight weeks following initiation, then every three to six months, and target the upper-quartile age-matched reference range rather than supraphysiologic values ^[12]. The 2010 study by Cordido and colleagues showing inverse correlation between peak GH response and HOMA-IR in obese subjects (R = −0.846, p = 0.001) is the contextual reason the metabolic-panel labs travel with the IGF-1 measurement ^[7].

§ VII · Adverse-event profile in the published trials

Adverse-event profile in the published trials

The FDA-approved Geref clinical-trial dataset documented that the most common treatment-emergent adverse event in pediatric subjects receiving thirty micrograms per kilogram of sermorelin subcutaneously nightly was a transient injection-site reaction (pain, swelling, or redness) occurring in approximately one in six patients ^[8]. Headache, flushing, dysphagia, dizziness, hyperactivity, somnolence, and urticaria each occurred at rates below one percent. No clinically significant changes in serum chemistries, thyroid function, or glucose tolerance were observed over the trial period ^[8].

The adult somatopause trials (Corpas 1992, Khorram 1997) and the cognitive trials (Vitiello 2006, Baker 2012) did not report significant adverse-event signals beyond transient injection-site reactions and occasional flushing — although these trials were short (two to twenty-four weeks) and small (nineteen to one hundred thirty-seven subjects) relative to a multi-year safety study ^{[2][3][4][16]}.

The historic Geref label listed active malignancy and unevaluated pituitary mass as contraindications — exclusion criteria that have carried into adult research populations. The site does not enumerate these as guidance but notes them as part of the historical regulatory record.