Novel therapeutic avenues for kisspeptin

Buy Lab Tests Online

madman

Super Moderator
Novel therapeutic avenues for kisspeptin (2022)
Jovanna Tsoutsoukia, Ali Abbarab, and Waljit Dhillo


Abstract

Kisspeptin is a hypothalamic neuropeptide that acts via the hypothalamus to stimulate hypothalamic gonadotrophin-releasing hormone secretion and downstream gonadotrophin release. In health, kisspeptin induces normal puberty and modulates ovulation in healthy women. Hypothalamic kisspeptin expression is reduced in several functional reproductive disorders; thus, treating such conditions with kisspeptin is conceptually attractive. Recent studies have demonstrated that kisspeptin can induce a more physiological degree of oocyte maturation during in vitro fertilization treatment that can reduce the risk of potentially life-threatening complications such as ovarian hyperstimulation syndrome seen with human chorionic gonadotrophin. Furthermore, chronic use of kisspeptin could potentially restore reproductive health in females with hypothalamic amenorrhoea, treat hyposexual drive disorder in otherwise healthy males, and has potential indications in polycystic ovary syndrome, osteoporosis, and metabolic dysfunction-associated fatty liver disease. Finally, kisspeptin analogs could potentially overcome some of the pharmacological challenges associated with the natural forms of kisspeptin such as short duration of action and development of tachyphylaxis.




Background

The kisspeptins are a family of peptides encoded by the KISS1 gene in humans (KISS1 in non-human primates and Kiss1 in other mammals) [1]. The prepropeptide consists of 145 amino acids that are subsequently proteolyzed into shorter peptides of lengths denoted by their suffixes, such as kisspeptin-54 (KP-54), -14, -13, and -10 (KP-10) [2]. All forms share a common C-terminal decapeptide sequence, equivalent to KP-10, which is important for their binding to the G-protein-coupled kisspeptin receptor, KISS1R (formerly known as the orphan receptor GRP54) [2]. Kisspeptin primarily stimulates the hypothalamus to regulate the hypothalamic-pituitary-gonadal axis [3]. Indeed, the decreased KISS1R signaling in humans results in absent puberty and hypogonadotropic hypogonadism [4,5], whereas increased KISS1R signaling results in precocious puberty [6]

Outside the human hypothalamus [7], kisspeptin and its receptor are expressed in the brain in key limbic and paralimbic regions [7], and in peripheral tissues such as the gonads, placenta, liver, adipose tissue, and bone [7].
Consequently, beyond its central role in stimulating hypothalamic gonadotrophin-releasing hormone (GnRH) secretion, kisspeptin has been studied in sexual and emotional brain processing [7], bone turnover [8], metabolism [9], and as a biomarker of pregnancy complications [10]. Herein, we summarise data on the pharmacological use of kisspeptin in reproductive disorders and fertility treatment, as well as its putative utility in hypoactive sexual desire disorder (HSDD), osteoporosis, and non-alcoholic fatty liver disease, now known as metabolic dysfunction-associated fatty liver disease (MAFLD) (Figure 1).





Kisspeptin trials in healthy men and women

KP-10, KP-54, and kisspeptin receptor agonists such as TAK-683 [11] and MVT-602 (formerly known as TAK448) [12] are the kisspeptin peptides that have been studied in humans to date. KP-10 is potent against KISS1R in vitro but is not believed to cross the blood-brain barrier and has a shorter half-life than KP-54 (t1/2 3 vs. 28 min) due to significant enzymatic degradation, making it less suitable for bolus administration [2]. Native KP-54 has a longer half-life and induces greater LH rises in vivo after bolus administration but is more expensive to manufacture than KP-10 due to its longer peptide length [13]. KISS1R-analogs, such as TAK-683 and MVT-602, which have been recently developed by modification of KP-10, possess increased stability and potency, hence enabling more cost-effective peptide manufacture [11,12].

Exogenous kisspeptin has been reported to potently stimulate GnRH and in turn luteinizing hormone (LH), in healthy men and women, and in patients with the reproductive disease, using different kisspeptin peptide forms (KP-54, KP-10, KP-analogue), durations, frequencies (bolus or continuous infusion) and administration routes (central, subcutaneous, intranasal or intravenous) [2,14-19]. Subcutaneous KP-54 stimulated gonadotrophin secretion in healthy females throughout all phases of their menstrual cycle [18,20,21], but with the greatest LH rises during the preovulatory phase [18,22e24]. Intravenous KP-10 was the least effective during the follicular phase of the menstrual cycle and evoked no gonadotrophin response when administered subcutaneously [25,26].

In healthy men, both an intravenous bolus and a continuous infusion of KP-10 produced significant LH responses with the latter maintaining LH secretion for at least 22.5 h [17,25]. Acute and chronic administration of intravenous KP-10-induced LH increases in obese hypogonadal diabetic men [27] and healthy older men [28], thereby highlighting promising therapeutic avenues for the use of kisspeptin in male functional hypogonadism related to diabetes, obesity, or age.

Recently, kisspeptin receptor agonists, including MVT-602 and TAK-683, were shown to potently increase LH secretion in men and women [12,29-31].
MVT-602 administered during the follicular phase of the menstrual cycle of healthy women triggered a similar LH amplitude to KP-54 yet produced a more sustained LH rise, with a correspondingly increased area under the curve of LH rise [12]. However, pharmacokinetic properties were similar between MVT-602 and KP-54, suggesting that the longer duration of effect was centered on differential activation of the kisspeptin receptor [12]. When studied in vitro on mouse GnRH neurons, MVT-602 was more potent and induced a more sustained duration of GnRH-neuronal firing than KP-54 (115 vs. 55 min) [12]. Importantly, kisspeptins have been administered to a few hundred patients by different research groups and to different populations but have not been associated with any adverse effects [11,15-17,32-34]. Indeed, kisspeptin levels increase dramatically during pregnancy from non-pregnant levels (8 pmol/L) to 1230 pmol/L during the first trimester and 9590 pmol/L during the third trimester [35e37], consistent with the reported wide therapeutic safety window [10].





Kisspeptin trials in reproductive disorders
-Kisspeptin trials in reproductive disorders Kisspeptin and oocyte maturation in in vitro fertilization treatment
-Kisspeptin and polycystic ovary syndrome
-Kisspeptin and hypothalamic amenorrhoea





Kisspeptin as a therapeutic in other conditions
-Kisspeptin and metabolic dysfunction-associated fatty liver disease
-Kisspeptin and hypoactive sexual desire disorder
-Kisspeptin and bone metabolism





Conclusion

Kisspeptin acts via the hypothalamus to stimulate endogenous GnRH secretion and downstream gonadotrophin release. Hypothalamic kisspeptin expression is reduced in several functional reproductive disorders, for example, hyperprolactinemia [58], obesity [71], and undernutrition-related hypogonadism [57]. Thus, treating such conditions with kisspeptin to replace the deficient kisspeptin is conceptually attractive.

Furthermore, kisspeptin is part of the physiological mechanism of ovulation [72] and thus can be used to restore ovulation in patients where this is lost. In this setting, it can induce a more physiological degree of stimulation that can reduce the risk of complications, such as OHSS seen with hCG. There is also increasing interest in the extra-hypothalamic actions of kisspeptin, such as in the ovary, where it may directly reduce VEGF secretion and further relieve the risk of OHSS.

In summary, kisspeptin could have therapeutic benefits in several clinical settings including the restoration of reproductive health in women with HA, as a trigger of oocyte maturation during IVF treatment, as a treatment for HSDD, as well as possible therapeutic indications in osteoporosis and MAFLD pending further clinical studies. The development of kisspeptin analogs has the potential to overcome some of the pharmacological challenges encountered using the natural forms of kisspeptin although further clinical trials are needed to realize this potential.
 

Attachments

  • 1-s2.0-S1471489222001461-main.pdf
    1.1 MB · Views: 48
Defy Medical TRT clinic doctor

madman

Super Moderator
Novel therapeutic avenues using kisspeptin. Kisspeptin has a putative therapeutic benefit in humans in reproductive anovulatory conditions (e.g. hypothalamic amenorrhoea (HA), polycystic ovary syndrome (PCOS), during in vitro fertilization (IVF) treatment, in the treatment of metabolic bone disease, in metabolic associated fatty liver disease (MAFLD), in hyposexual drive disorder (HSDD) and as a biomarker to predict pregnancy complications such as miscarriage. Created with BioRender.com.
Screenshot (18890).png
 

madman

Super Moderator



 
Buy Lab Tests Online

Sponsors

bodybuilder test discounted labs
Defy Medical TRT clinic
nelson vergel coaching for men
Discounted Labs
TRT in UK Balance my hormones
Testosterone books nelson vergel
Register on ExcelMale.com
Trimix HCG Offer Excelmale
Thumos USA men's mentoring and coaching
Testosterone TRT HRT Doctor Near Me
how to save your marriage

Online statistics

Members online
4
Guests online
5
Total visitors
9

Latest posts

Top