The Known and Unknown of Leptin in Pregnancy and Gynaecological Problems,
Prof. Haleema A. Hashmi, MBBS, MRCOG (UK), FRCOG (UK), FCPS (PK)
Liaquat National Hospital & Medical College, Karachi, Pakistan.
Abstract:
Leptin is a vital peptide hormone secreted by the adipose tissue, which has been regarded for years as an exclusive regulator of energy and satiety homeostasis. It’s role in pregnancy was recognized only during the last three decades. Leptin is now proven to play a wide range of roles in reproductive biology, from maternal physiology to implantation and from paracrine effects in placenta to regulation of conceptus development and fetal growth. The role of leptin in pregnancy was suggested by the findings that plasma levels during gestation are greater, it is synthesized within the feto-placental unit, and due to its interaction with common pregnancy pathologies. It is involved in regulation of GnRH and LH secretion and in puberty and lactation. Leptin disorders can lead to reproductive disorders, including infertility, recurrent pregnancy loss and polycystic ovarian syndrome. We review the known and unknown of leptin in metabolic regulation of the reproductive axis.
•Protein with tertiary structure of a cytokine
•Encoded by ob gene located on chromosome 7
•Expressed predominantly by adipocytes; smaller amounts secreted by stomach epithelial cells and in the placenta
•Leptin receptors are highly expressed in:
•Hypothalamus- regulates body weight
•T- lymphocytes and vascular endothelial cells
• Four isoforms; Ob-Rb is expressed in endometrium, myometrium, placenta & umbilical cord.
Leptin in Pregnancy
Leptin hormone is produced, and leptin receptors are expressed by the human placenta
Human placental leptin is identical to adipose tissue leptin. Leptin increase precedes the increase in BMI.
Leptin in Diabetes
•Leptin production is stimulated by hyperinsulinemia
•Dramatic increase in fetal and placental leptin concentration correlates with higher inflammatory cytokines, IL6 & TNF-a.
•Mitotic activity and growth signals through Mitogen-activated protein kinase activation à macrosomia
Leptin in Disorders of Placental Growth
•Molar pregnancy and choriocarcinoma are associated with maternal leptinemia; leptin levels decrease after evacuation
•Decreased leptin levels – intrauterine growth restriction (fat mass only 3-5% of total body weight
Functions and Regulation of Leptin
•Leptin provides a link between the immune and endocrine system responses of the placental cells
•Contributes to placental angiogenesis, erythropoiesis & induces placental growth to produce hCG
•Suppresses rejection of developing fetus
•Regulates fetal growth (maternal leptin does not significantly cross placenta. Fetal leptin is produced by fetal adipose tissue2 from 18 weeks gestational age)
•Insulin acts as a regulator of placental gene; hypoxia is also a stimulus. Leptin resistance, like insulin, can occur
Leptin in Pre-eclampsia
•Increased placental synthesis but low umbilical concentration; increased maternal leptin concentration
•Leptin may also modify arterial thrombosis after endothelial injury through interaction with platelet leptin receptors
Leptin in Gynaecological Disorders
•Leptin in puberty and menstruation
•Cyclical variation in serum leptin
concentration correlating with pulses
of menstrual cycle
•Lower leptin level due to heavy
exercise & decreased body fat; lower
leptin level can lead to amenorrhoea;
resumption with recombinant leptin therapy
•Leptin receptor deficiency caused
by LEPR gene mutation can lead to
hypogonadotrophic hypogonadism, delayed puberty / no puberty
•Role in infertility
•Central Nervous System: Controls reproduction by acting on hypothalamus; leptin receptors are present in GnRH producing cells; release of FSH & LH from pituitary is governed by central pathway involving leptin
•Ovaries: High leptin levels suppress oocyte maturation
•Endometrium: Receptivity of endometrium blunted under the effect of leptin (in obese women) as well as normal decidualisation
•Embryo: Affects implantation and growth of developing embryo; lower success rates of in-vitro fertilization in obese women
•Leptin in Polycystic Ovarian Syndrome (PCOS): Increased LH levels are associated with increased leptin levels in PCOS (studies sparse on a direct cause for PCOS)
•Leptin and recurrent pregnancy loss (RPL): Leptin signaling pathway defects - a possible cause of idiopathic RPL; raised serum leptin levels in women with RPL; however, low level also seen; link between leptin and RPL is inconclusive
The UNKNOWN of Leptin
•Reason for elevated leptin levels during normal pregnancy?
•Is excess leptin beneficial or detrimental for the fetus?
•Does leptin participate in fetal programming of obesity and adult disease?
Does leptin regulate fetal fat accretion or does such control require interaction between adipose tissue and central brain targets in utero?
•Role of increased maternal leptin level and fetal umbilical prolactin level is not clear
Conclusion
•Leptin is the cross-talk molecule linking human reproduction and nutrition
•Will ob protein be useful for treating human obesity?
•Recombinant leptin therapies and leptin sensitizers should be grounds for further research to address the serious effects of leptin and leptin resistance on reproduction.
