Control of human luteal steroidogenesis

doi:10.1016/S0303-7207(01)00654-2

Molecular and Cellular Endocrinology

Volume 186, Issue 2, 25 January 2002, Pages 137-141

https://doi.org/10.1016/S0303-7207(01)00654-2 Get rights and content

Abstract

The human corpus luteum (CL) undergoes a dynamic cycle of differentiation, steroid hormone production and regression during the course of non-fertile cycles. In humans and other primates, luteal steroidogenesis is absolutely dependent on pituitary-derived LH. However, changes in LH and LH receptor expression do not explain the marked decline in progesterone production at the end of the luteal phase. Changes in the level of the steroidogenic acute regulatory protein (StAR), a gene whose expression is controlled by LH most likely account for the cyclic pattern of progesterone production. During the mid-to-late luteal phase of a fertile cycle, chorionic gonadotropin (hCG) rescues the CL, overcoming the actions of the factors inducing luteolysis. Although the agents causing regression of the CL in a non-fertile cycle are not yet known, intra-luteal growth factors and cytokines that modify the action of LH probably contribute to the reduction of StAR expression and the subsequent fall in progesterone production.

Introduction

The human corpus luteum (CL) is a remarkable steroidogenic gland that produces up to 40 mg of progesterone daily, reflecting a highly efficient steroidogenic machinery. Luteal steroidogenesis is required for the development of endometrial receptivity and maintenance of early pregnancy. The primate CL is composed of steroidogenic cells (theca- and granulosa-lutein) and non-steroidogenic cells (endothelial, immune, fibroblast), both of which are essential for the synthesis and secretion of steroids. Unique to the CL of many primates, including the human, is the secretion of significant amounts of androgens and estradiol, as well as progesterone (Hild-Petito et al., 1989, Retamales et al., 1994). The production of these hormones is largely dependent on pituitary-derived LH, acting through the cAMP second messenger signaling system to regulate genes essential for hormone synthesis and luteal development. During the cycle of conception, trophoblastic production of human chorionic gonadotropin (hCG) prevents the regression of the CL. Even though LH is essential for the development and maintenance of the primate CL, luteal regression is not due to changes in LH pulse frequency or amplitude (Hutchison and Zeleznik, 1986).

This suggests that the actions of LH are regulated by intraluteal factors. Indeed, the effects of LH/hCG on luteal cell steroidogenesis are modified by a variety of molecules encompassing growth factors, hormones, nitric oxide, cytokines and IGF binding proteins (Devoto et al., 2000, Fraser et al., 2000). The rate-limiting step in steroid hormone synthesis is the delivery of cholesterol from the outer to the inner mitochondrial membrane, where the cytochrome P₄₅₀ cholesterol side chain cleavage (P_{450 scc}) system is located. The translocation of cholesterol substrate is promoted by StAR a phosphoprotein expressed in steroidogenic cells (Strauss and Penning, 1999).

Section snippets

The steroidogenic activity of subpopulations of luteal cells

The cells comprising the CL have different morphological, endocrine and biochemical features. Histological examination of the CL reveals small (theca lutein) and large (granulosa-lutein) cells, fibroblasts, endothelial and immune cells. The number, morphology, function and secretory capabilities of these cells change throughout luteal phase. Approximately 30% of these cells are steroidogenic (Devoto et al., 2000). Small luteal cells are hypothesized to be derived from the theca-interna while

Non-steroidogenic luteal cells

Approximately 30–40% of the cells in a mature CL are endothelial cells. The abundance of this cell type is related to the extensive capillary network within the CL. Although the luteal vasculature is recognized to be critical for the delivery of substrate (plasma lipoproteins) to, and removal of secretory products (steroid hormones) from luteal cells, the mechanisms regulating its development and demise are poorly understood. Recently, Fraser et al. (Fraser et al., 2000), showed that IGFBP-3

Effect of LH and hCG on the primate corpus luteum

Several studies have examined the role of LH pulse amplitude and frequency in the maintenance of the primate CL. During the early luteal phase, frequent pulses of low amplitude have been observed, whereas by the mid-luteal phase, LH pulses are less frequent but are of greater amplitude. A progesterone peak occurs after each LH pulse during mid-late luteal phase (Filicori et al., 1984). LH/hCG binds to and activates a specific glycoprotein hormone receptor on the membrane of the steroidogenic

Expression of P_{450 scc} and 3β-HSD in human corpora lutea

Cholesterol is converted into pregnenolone in the cholesterol side-chain cleavage reaction, which is catalyzed by P_{450 scc} and its associated electron transport proteins. The relatively constant expression of the 2 kb P_{450 scc} mRNA transcript throughout the luteal phase suggests that alterations in P_{450 scc} expression are unlikely to be responsible for cyclical changes in luteal steroidogenesis (Duncan et al., 1999).

Similar to P_{450 scc} expression, the 1.7 kb 3β-HSD mRNA transcript is also

Expression of steroidogenic acute regulatory protein in human corpora lutea

The steroidogenic acute regulatory protein governs the rate-limiting step in steroidogenesis, which is the translocation of cholesterol from the outer to the inner mitochondrial membrane. Thus, to comprehend the significant steroidogenic changes that occur during human luteal phase, it is important to define StAR gene expression within the CL. Steroidogenic acute regulatory protein is not highly expressed in granulosa cells of the preovulatory follicle (Kiriakidou et al., 1996). Therefore, the

Acknowledgements

This work was supported in part by Fondecyt Grant 1-99-0042, and NIH grants HD-062274, TW/HD00671.

References (23)

M. Brannstrom et al.
Variations in peripheral blood levels of immunoreactive tumor necrosis factor α (TNFα) throughout the menstrual cycle and secretion of TNFα from the human corpus luteum
Eur. J. Obstet. Gynecol. Reprod. Biol.
(1999)
L. Devoto et al.
Regulation of steroid hormone synthesis by human corpora lutea: failure of follicle-stimulating hormone to support steroidogenesis in vivo and in vitro
Fertil. Steril.
(1989)
P.H. Chung et al.
Hormone and Prostaglandin F2α regulation of messenger ribonucleic acid encoding steroidogenic acute regulatory protein in human corpora lutea
Endocrine
(1998)
L. Devoto et al.
Multihormonal regulation of progesterone synthesis in cultural human midluteal cells
J. Clin. Endocrinol. Metab.
(1995)
L. Devoto et al.
Insulin and insulin-like growth factor-I and II modulate human granulosa-lutein cell steroidegenesis: enhancement of steroidogenic acute regulatory protein (StAR) expression
Mol. Hum. Reprod.
(1999)
L. Devoto et al.
Endocrine, paracrine-autocrine regulation of the human corpus luteum during mid-luteal phase
J. Reprod. Fertil. Suppl.
(2000)
W.C. Duncan et al.
Luteinizing hormone receptor in the human corpus luteum: lack of down-regulation during maternal recognition of pregnancy
Hum. Reprod.
(1996)
W.C. Duncan et al.
Steroidogenic enzyme expression in human corpora lutea in the presence and absence of exogenous human chorionic gonadotropin (hCG)
Mol. Hum. Reprod.
(1999)
M. Filicori et al.
Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion
J. Clin. Invest.
(1984)
H.M. Fraser et al.
Changes in insulin-like growth factor binding protein-3 messenger ribonucleic acid in endothelial cells of the human corpus luteum: a possible role in luteal development and rescue
J. Clin. Endocrinol. Metab.
(2000)

S.A. Hild-Petito et al.

Isolation and characterization of cell subpopulations from the monkey corpus luteum of the menstrual cycle

Biol. Reprod.

(1989)

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Control of human luteal steroidogenesis

Abstract

Introduction

Section snippets

The steroidogenic activity of subpopulations of luteal cells

Non-steroidogenic luteal cells

Effect of LH and hCG on the primate corpus luteum

Expression of P450 scc and 3β-HSD in human corpora lutea

Expression of steroidogenic acute regulatory protein in human corpora lutea

Acknowledgements

Eur. J. Obstet. Gynecol. Reprod. Biol.

Fertil. Steril.

Hormone and Prostaglandin F2α regulation of messenger ribonucleic acid encoding steroidogenic acute regulatory protein in human corpora lutea

Endocrine

Multihormonal regulation of progesterone synthesis in cultural human midluteal cells

J. Clin. Endocrinol. Metab.

Insulin and insulin-like growth factor-I and II modulate human granulosa-lutein cell steroidegenesis: enhancement of steroidogenic acute regulatory protein (StAR) expression

Mol. Hum. Reprod.

Endocrine, paracrine-autocrine regulation of the human corpus luteum during mid-luteal phase

J. Reprod. Fertil. Suppl.

Luteinizing hormone receptor in the human corpus luteum: lack of down-regulation during maternal recognition of pregnancy

Hum. Reprod.

Steroidogenic enzyme expression in human corpora lutea in the presence and absence of exogenous human chorionic gonadotropin (hCG)

Mol. Hum. Reprod.

Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion

J. Clin. Invest.

Changes in insulin-like growth factor binding protein-3 messenger ribonucleic acid in endothelial cells of the human corpus luteum: a possible role in luteal development and rescue

J. Clin. Endocrinol. Metab.

Isolation and characterization of cell subpopulations from the monkey corpus luteum of the menstrual cycle

Biol. Reprod.

Expression of P_{450 scc} and 3β-HSD in human corpora lutea