Mechanisms of Luteinising Hormone Regulation in Female Steroidogenesis

Review Article

Austin Gynecol Case Rep. 2017; 2(1): 1008.

Mechanisms of Luteinising Hormone Regulation in Female Steroidogenesis

Cadagan D*

Department of Sciences, Staffordshire University, England

*Corresponding author: Cadagan D, Lecturer in Biomedicine, Senior Biomedical Researcher, Department of Sciences, Staffordshire University, England

Received: June 10, 2016; Accepted: January 10, 2017; Published: January 12, 2017


Understanding the mechanisms of steroidogenic regulation in female fertility is fundamental to determining dysfunction. Research has revealed a strong relationship between fertility and metabolic disturbances. With many endocrine signals involved in activation of steroidogenic cascades, it has become necessary to map the complex cross-talk between these regulatory systems and this review looks to establish this based on current understanding. Luteinising hormone is a vital endocrine hormone that is already known to signal via these pathways, although its involvement in metabolic disturbance is less understood. Studies investigating activation of the LH receptor in key steroidogenic cells, ovarian theca and granulosa, have highlighted overlaps in important signalling cascades including PKC/MAPK/PKA and PI3K. Here, we review LH and its signalling cross-talk in key steroidogenic pathways.

Keywords: Luteinising hormone (LH); Lutropin; Steroidogenesis; Gonadotropin; Ovulation; LH Receptor; Cyclic adenomonophosphate (cAMP); Diacylglycerol (DAG); Protein kinase C pathway; MAPK pathway


The pituitary gland is responsible for secretion of various endocrine signalling hormones with the anterior pituitary producing somatotropins, thyrotropins, corticotropins, lactotropins and gonadotropins. Dysfunction of the pituitary gland can therefore have systemic effects as a result of signalling errors and conditions such as hyper and hypopituitarism. These dysfunctions have been linked to the pathophysiology of conditions such as diabetes and the metabolic syndrome. There has been a rapid increase in Diabetes Mellitus (DM) over the past decades resulting in it becoming one of the most prevalent endocrine disorders, effecting ~135 million people. Therefore, it is vital to understand the mechanisms behind the condition [1,2].

Many studies have examined the effect of diabetes on gonadotropin production with an aim of determining a relationship between impaired fertility and menstrual disturbances [3-5]. In doing so, the importance of Luteinising Hormone (LH) in pituitary regulation has been highlighted, as well as its sensitivity to metabolic changes [1]. Although reduced gonadotropin response may play only a partial role in steroidogenic function it is important to understand the mechanism and pathways involved in order to fully understand the overall dysfunction.

This review will examine our current understanding of the effects of LH on steroidogenic cells to allow future mapping of possible regulatory pathways that may be seen as targets for dysfunction in metabolic diseases.

Luteinising Hormone and Steroidogenesis

The gonadotropins are a family of proteins consisting of LH, Follicular Stimulating Hormone (FSH) and the Chorionic Gonadotropins (CG). These hormones are vital in the control and regulation of reproductive function in males and females. LH and FSH are secreted by the anterior pituitary gland, whereas CG is produced by a component of the fertilised egg called the Syncytiotrophoblast. LH, also known as lutropin, stimulates ovulation and development of the corpus luteum females. Structurally LH is a heterodimeric glycoprotein similar in structure to FSH, thyroid stimulating hormone and Human Chorionic Gonadotropin (hCG). All four proteins share a common alpha subunit, with the beta subunits conferring biological specificity [6,7].

In females, FSH action on ovarian granulosa cells initiates follicular growth. This stimulates a rise in oestrogen and LH receptor expression. Eventual positive feedback to the hypothalamus occurs, resulting in the release of LH over a 24-48hr period. The ensuing LH surge triggers ovulation, releasing the egg and initiating the production of the corpus luteum from the remnants of the follicle. The corpus luteum secretes progesterone for endometrial preparation and the possibility of implantation. LH is maintained for up to two weeks allowing for steroidogenesis along with support via hCG action. In the case of pregnancy LH supports theca cells which produce androgens necessary for estradiol synthesis and cell proliferation [3,7].

LH Receptor

Luteinising hormone / chorionic gonadotropin activates multiple signal transduction systems. The luteinising hormone receptor is part of the Glycoprotein Hormone Receptor Family (GpHRs) which also includes Follicular Stimulating Hormone Receptor (FSHR) and Thyroid Stimulating Hormone Receptor (TSHR). The LH receptor differs from these through its ability to bind two glycoprotein hormones, LH and hCG. These receptors are responsible for regulation of reproductive and metabolic processes with LHR activation leading to androgen synthesis and ovulation. The GpHRs contain two major domains of approximately the same size. Firstly, a large, glycosylated N-terminal Ectodomain (ECD) containing Leucine-Rich Repeats (LRRs) capped by cys-rich regions, the latter forming a portion of a hinge region. Secondly, a Trans-Membrane domain (TM) with seven membrane spanning helices, three extracellular loops (ecls), three intracellular loops (icls) and a short icl 4, an eighth cytoplasmic helix parallel to the plasma membrane, and a cytoplasmic tail [3]. The ECD and TM domains have important and distinct functional roles, namely hormone binding and signal transduction, respectively [8,9].

Most of the sequential steps involved after hormone binding to the ECD until G protein activation on the inner face of the plasma membrane remain poorly understood. In many experimental systems, LH or hCG binding to LHR results in activation of both protein kinase A and protein kinase C. At relatively low concentrations of LH and hCG, Gs appears to be the preferred signalling pathway, resulting in a rapid increase in the intracellular concentration of cAMP [10].

Cyclic Adenomonophosphate

cAMP is derived from adenosine triphosphate and is utilised within intracellular signal transductions as a second messenger, transferring the effects of hormones incapable of permeating cellular membranes. Typically, it allows activation of protein kinases and is also involved in the release of intracellular calcium from the endoplastic reticulum.

cAMP synthesis occurs through adenlyl cyclase action on ATP located on the inner plasma membrane and decomposition occurs through phosphodiesterase action on cAMP. This action occurs through stimulatory G-protein (Gs)-coupled receptor activation and is inhibited by agonists of adenylyl cyclase inhibitory G (Gi)-proteincoupled receptors.

Adenylate cyclase can be activated or inhibited by G proteins, which are coupled to membrane receptors and thus can respond to hormonal or other stimuli. Following activation cAMP acts as a second messenger by interacting with and regulating other proteins such as protein kinase A and cyclic nucleotide-gated ion channels [11,12].

Studies in pre-pubertal female rats have shown that in conditions such as uraemia can lead to reduced gonadtropin - cAMP sensitivity. This condition is related to metabolic disturbance and has direct associations to diabetes mellitus and diabetes induced cardiac failure as well as chronic kidney failure [13]. Furthermore, female uremic patients have shown menstrual irregularities and cases of delayed puberty possibly associated with gonadotropin target response. However, research in uremic premenopausal women has also shown hormonal disturbances including an absence in pre-ovulatory peaks of LH and estradiol concentrations. The source of these irregularities may therefore originate within the hypothalamus via impaired production of GnRH or in the anterior pituitary rather than within the cellular targets [14].

Diacylglycerol / Protein Kinase C Pathway

Diacylglycerol (DAG) is a key second messenger that regulates important cellular responses including proliferation, apoptosis, immune response and differentiation. This occurs via its target protein Protein Kinase C (PKC). Activation is linked to the LH receptor as a hepta-membrane spanning protein that couples stimulatory binding proteins Gs and Gq to allow adenylate cyclise signalling and increases in cAMP. This subsequently activates cAMP dependent PKA [11,12].

LH receptor activation increases intracellular calcium as a result of Phospholipase C activation (PLC) [5,15]. Once activated PLC allows cleavage of phosphatidylinsitol, 4,5-biphospate into inositol- 1,4,5-triphosphate (IP3) and Diacyglycerol (DAG). IP3 then binds to intracellular calcium channels on the endoplasmic reticulum resulting in increased cytosoliccalcium levels. DAG binds to Protein Kinase C (PKC) allowing co-activation (Figure 1) [16,17]. PKC requires calcium, phosphatitylserine and DAG for activation. These regulators allow a conformational change revealing the substrate binding site [18].

Citation: Cadagan D. Mechanisms of Luteinising Hormone Regulation in Female Steroidogenesis. Austin Gynecol Case Rep. 2017; 2(1): 1008.