Humanin: An Alternative Therapy for PCOS

 

A common hormonal condition affecting more than 10% of women, is PCOS (Polycystic Ovary Syndrome). The three clinical criteria of PCOS are:

1.     Evidence of excess male type hormones, noted either by having elevated blood hormones levels of androgens (hyperandrogenism) or excess growth of facial or body hair in areas where men usually have hair

2.     Irregular periods with menstrual cycles more than 35 days apart or eight or fewer menstrual cycles per year not due to hormonal birth control

3.     The presence of a high number of eggs on an ovarian ultrasound  

A woman with two of the three above criteria may be diagnosed with PCOS

PCOS may often lead to infertility, insulin resistance (IR), obesity, and metabolic disturbances. Around 50 to 70% of women diagnosed with PCOS, showcase IR. Insulin resistance is a condition wherein cells fail to respond properly to the Insulin hormone thus increasing blood sugar levels. The body attempts to maintain the stability of blood glucose by secreting excessive insulin, this results in a condition termed hyperinsulinemia. IR can also further lead to metabolic syndrome and type 2 diabetes. Previous studies have reported that PCOS patients are more likely than healthy women to have impaired glucose tolerance, IR, and type 2 diabetes.

Humanin (HN) is a mitochondrial-derived peptide initially discovered in 2001 by Hashimoto using a cDNA library of an Alzheimer's patient brain. HN was the first small open reading frame (ORF) identified within the mitochondrial DNA, encoded within the 16S rRNA gene (MT-RNR2). . Humanin has various biological functions, including anti-apoptotic, anti-oxidative stress, and anti-inflammatory actions. Several studies have reported that humanin and its analogue, S14G-humanin (HNG), have regulatory effects on peripheral insulin action, and may therefore function as insulin sensitizers. Previous studies have confirmed the expression of humanin in the female reproductive system, including the follicular fluid and multiple types of ovarian cells, and showed that humanin expression levels are associated with clinical outcomes of assisted reproductive technology. This leads to a question of whether humanin expression in the ovaries differs between PCOS patients with and without IR.

Blood samples were collected on days 2 to 4 of menstruation, from 47 women diagnosed with PCOS, and 36 non-PCOS women. The non-PCOS women served as control group for this particular study. These 83 women were divided into 4 sub-groups: PCOS with IR (PCOS + IR), PCOS without IR (PCOS − IR), non-PCOS with IR (non-PCOS + IR), and non-PCOS without IR (non-PCOS − IR), respectively. These 4 groups had similar serum humanin concentrations, but significantly different follicular fluid humanin concentrations. Patients in the PCOS + IR group had significantly lower follicular fluid humanin concentrations than those in the PCOS − IR group. In non-PCOS patients, IR was also associated with a non-significantly lower follicular fluid humanin concentration. After adjustment for age, the PCOS + IR patients also had significantly lower follicular fluid humanin concentrations than the PCOS − IR patients. Correlations between the patients’ characteristics and follicular fluid humanin concentrations were analyzed in both PCOS and non-PCOS patients. In PCOS patients, the basal total testosterone level, FINS concentration, and HOMA-IR index value were negatively associated with the follicular fluid humanin concentration. However, these associations were not present in the corresponding data for non-PCOS patients.

Upon insulin stimulus, glucose transporter type 4 (GLUT4) rapidly translocates to the cell surface from the cytoplasm. This translocation results from the activation of various protein kinases, including insulin receptor substrate 1 (IRS1), phosphoinositide 3–kinase (PI3K), and protein kinase B (PKB/Akt). Abnormal IRS1/PI3K/ Akt signaling pathway activity, (for example, decreased IRS1 expression and phosphorylation) is commonly observed in PCOS patients with IR. This condition leads to the translocation disorder of GLUT4, which, in turn, results in glucose transport dysfunction and ultimately IR.

GLUT4 is a high-affinity glucose transporter that is predominantly expressed in insulin-sensitive tissues. In response to insulin or exercise, GLUT4 dissociates from GLUT4 storage vesicles and translocates to the plasma membrane, which results in a 10-fold increase in glucose uptake. Through fluorescent microscopic analysis, it was observed that the addition of HNG increased the expression of GLUT4 and promoted its translocation to the cell membrane.

In this study, it was demonstrated that local ovarian humanin expression is downregulated in PCOS patients with IR relative to its expression in PCOS patients without IR. Currently, there is no approved therapy for PCOS because of its complex pathogenesis and associated metabolic disorders. Because IR is a key indicator of the progression of PCOS, insulin sensitizers, such as metformin, have been used for the management of PCOS. However, metformin treatment is not indicated for all patients. This drug has gastrointestinal side effects, and studies have reported that in utero exposure to metformin increases the risk of obesity in childhood. Therefore, humanin is anticipated to be an alternative therapy for PCOS patients with IR in clinical settings in the future.

REFERENCES:

Wang Y, Zeng Z, Zhao S, Tang L, Yan J, Li N, et al. Humanin Alleviates Insulin Resistance in Polycystic Ovary Syndrome: A Human and Rat Model-Based Study. Endocrinology [Internet]. 2021 Mar 10 [cited 2022 Dec 7];162(8).

IMAGE REFERENCES:

https://uthealthaustin.org/blog/q-a-polycystic-ovary-syndrome

 

 

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