Introductory Chapter: Progesterone

Abstract

Progesterone as steroid participates in the female menstrual cycle of humans and other animals, supporting pregnancy and embryogenesis. Progesterone facilitates secretory endometrium transition, promotes blastocyst implantation, and is crucial for maintaining pregnancy. Progesterone is crucial to non-reproductive tissues, including mammary glands during pregnancy, and bones. Over the past decades, research has primarily focused on genomic/non-genomic mechanisms, enabling us to further understand its role and clinical applications in HR) and diabetic neuropathy. This chapter provides an overview of the biosynthesis, physiological functions, and regulatory mechanisms of progesterone, with the aim of enhancing the understanding of its safety and efficacy in various physiological and pathological contexts, thereby serving as an important reference for its clinical application.

1. Introduction

Progesterone as a steroid participates in the female menstrual cycle of humans and other animals, supporting pregnancy and embryogenesis. It is one of the most essential progestogens. In non-pregnant women, progesterone is primarily secreted by corpus luteum (CL). During pregnancy, the placenta also secretes substantial amounts of progesterone. Additionally, the brain, liver, and adrenal glands secrete progesterone.

Steroid hormones are ancient molecules that regulate and interact with primitive cells, with cholesterol serving as a common precursor for all steroid hormones. The biosynthetic pathways of steroid hormones are consistent across various steroid-producing organs, such as the ovaries, testes, and placenta. However, the types and quantities of steroid hormones synthesized depend on specific enzymes in each organ.

Most gonadal-derived progesterone exerts its biological functions via blood transport, while most adrenal-derived progesterone is converted into glucocorticoids and androgens. The half-life of progesterone is very short, approximately 5 minutes, which is primarily metabolized in the liver and excreted in the urine.

Progesterone facilitates secretory endometrium transition, promotes blastocyst implantation, and is crucial for maintaining pregnancy. Progesterone is crucial to non-reproductive tissues, including mammary glands during pregnancy, and bones. Over the past decades, research has primarily focused on genomic/non-genomic mechanisms, enabling us to further understand its role and clinical applications in HR and diabetic neuropathy.

This chapter provides an overview of the biosynthesis, physiological functions, and regulatory mechanisms of progesterone, with the aim of enhancing the understanding of its safety and efficacy in various physiological and pathological contexts, thereby serving as an important reference for its clinical application.

2. The synthesis of progesterone

The synthesis of progesterone involves three consecutive steps [1, 2, 3]: (1) the STAR transports cholesterol to the inner mitochondrial membrane; (2) the P450SCC converts them into pregnenolone; (3) the 3β-HSD further converts them into progesterone. Notably, progesterone is the substrate of most steroids (Figure 1).

Figure 1.

The synthesis of progesterone and some other steroid hormones.

The STAR, P450SCC, and 3β-HSD are vital for the synthesis of progesterone [1, 2, 3]. Additionally, GST A1-1 and A3-3 synergistically produce progesterone with 3β-HSD. NR5A family members SF-1 and LRH-1 are also crucial [4, 5].

STAR acts as a cis-regulatory element for genes related to progesterone production, which is the steroidogenesis rate-limiting step [6]. Also, STAR regulation is extensively characterized [7, 8]. NR5A can bind to the STAR promoter and then activate STAR transcription [7].

P450SCC is an enzyme crucial for the initial step in the steroidogenesis pathway, located within the mitochondria. Transgenic mice carrying a segment approximately 2.3 kb upstream of the human CYP11A1 gene exhibit tissue-specific and gonadotropin-dependent expression [9]. Alongside the NR5A binding site in the promoter, the construct also contains a cAMP response sequence and an adrenal enhancer as cis-regulatory elements within the 2.3 kb segment [10].

3β-HSD has two isoforms, placental HSD3B1 and gonadal HSD3B2 [11]. The promoter of human HSD3B2 contains the NR5A binding site, which is crucial to cAMP-stimulated transcription [11].

Besides above, several NR5A regulatory genes contribute to progesterone synthesis. Human GST, ALAS1, FDX1, and FDXR have been identified as proteins related to steroidogenesis.

3. The functions of progesterone

The role of progesterone can be categorized into two primary functions: its role in reproductive system tissues, such as the ovaries and endometrium, and its function in non-reproductive system tissues, including the central nervous system and bones (Figure 2).

Figure 2.

The physiological and pathological functions of progesterone.

3.1 The role of progesterone in reproductive system tissues

In the late 1960s, Ryan and Petro proposed the “two-cell two-gonadotropin theory” [12], which advanced the understanding of progesterone’s role in the menstrual cycle. Specifically, LH stimulates follicular cells to synthetize androstenedione and subsequently converted into estrogen via follicle-stimulating hormone and the aromatase enzyme system [13]. Prior to ovulation, follicles synthesize estrogen and progesterone, which interact with membrane receptor PGRMC1 to promote follicle growth and inhibit apoptotic genes by directly affecting granulosa cells [14, 15]. Following the LH peak-induced ovulation, the CL forms [16]. During the follicular phase of the typical menstrual cycle, progesterone concentration remains below 1 ng/mL and then increases to 10 ~ 35 ng/mL within a few days after ovulation [17]. Additionally, PCOS ovarian luteinizing granulosa cells exhibit impaired ability to synthesize and secrete progesterone [18].

Progesterone is critical to the secretory endometrium transition. Throughout the menstrual cycle, the receptor expression of estrogen/progesterone in the endometrium varies. During the proliferative phase, PRs are primarily located in the epithelial cells of the endometrium. These receptors increase exponentially during ovulation in response to estradiol and subsequently decrease sharply [19, 20]. During the secretory stage, the endometrium undergoes combined effects of estrogen and progesterone. Progesterone halts endometrial growth by decreasing the cell mitotic activity [21, 22]. Additionally, progesterone exerts a protective effect on the endometrium of perimenopausal/postmenopausal women undergoing HRT [23].

During conception and early pregnancy, progesterone levels remain relatively stable but increase significantly in later stages, reaching 100–300 ng/mL. In the first nine-week pregnancy, progesterone is predominantly secreted by CL [23]. Subsequently, placental cells synthetize progesterone, making it the primary source after 12 weeks of gestation [24, 25]. Progesterone inhibits uterine contractions and suppresses immune responses at the maternal-fetal interface [25]. Approximately 35% of recurrent miscarriage cases are associated with luteal deficiency syndrome [24].

3.2 The role of progesterone in non reproductive system tissues

Progesterone significantly affects reproductive system tissues and also influences various other organs, thus being classified as a ‘neurosteroid hormone’ [26, 27, 28].

In CNS, progesterone regulates LH secretion within the hypothalamic-pituitary-adrenal axis, thereby developing a steroidogenesis feedback [29].

In breast tissue, progesterone facilitates the development of breast lobules and acini. Their mitotic activities are elevated in the follicular stage and decreased in the luteal stage. Progesterone also exerts a protective effect on breast tissue [30].

In blood glucose metabolism, progesterone can raise basal insulin and enhances its release following carbohydrate intake [31]. Progesterone secreted by the placenta elevates maternal blood glucose levels, which in turn increases fetal nutrient intake [28].

In osteoporosis, PRs express in osteoclasts and osteoblasts [32]. Progesterone inhibits bone resorption by directly stimulating calcitonin secretion and provides a nutritional benefit to bones similar to that of estrogens [32].

4. The mechanism of progesterone action

Progesterone primarily mediates its physiological and pathological effects by binding to specific progesterone receptors (PR) in the nucleus [30, 33]. PR is nuclear receptor, with two homologous receptors identified: 94 kDa PR-A and 114 kDa PR-B [30]. PR-A/B are transcripts encoded by a same gene, activated by distinct estrogen-induced promoters. Their functional characteristics and responses to progesterone differ [30]. For instance, PR-A can inhibit the transcriptional activity of other steroid hormone receptors, including estrogen receptors and PR-B [11, 33, 34]. Current research indicates that progesterone operates through two mechanisms: genomic/nuclear and non-genomic/extranuclear receptor pathways (Figure 3).

Figure 3.

The mechanism of progesterone action (created with BioRender.com).

In the genomic receptor mechanism, PR-A/B share DNA and ligand-binding domains [34]. Lipophilic molecule progesterone diffuses through the membrane to interact with specific PRs in the nucleus, activating approximately 300 co-regulators influencing rRNA and protein synthesis [33]. The nuclear PRs require several minutes to hours to activate transcription, which serves as a primary regulator in reproductive function [34].

In non-genomic receptor mechanisms, progesterone rapidly activates multiple secondary messengers to exert its effects and is not affected by steroid nuclear receptor inhibitors [34]. The non-genomic receptor for progesterone located on the cell membrane is termed PGRMC1. Its interaction with SERBP1 mediates the anti-apoptosis of progesterone [35]. PGRMC1 and SERBP1 are implicated in ovarian cancer. Limited information is regarding PGRMC2, which is regulated by gonadotropins [35].

During progesterone action, these genomic/non-genomic mechanisms can collaborate to directly affect cells and tissues.

5. Conclusion and prospect

Progesterone should be considered not only essential in the reproductive field but also a potential therapeutic agent for various clinical diseases, such as osteoporosis and diabetic neuropathy. Further understanding genomic/non-genomic receptor mechanisms will provide a comprehensive assessment of progesterone safety and efficacy in HRT, potentially reducing the risk of breast cancer. Additionally, a thorough understanding of progesterone’s biological role will facilitate its safe and effective application across various scientific and medical fields.

Abbreviation

ALAS1	5-aminolevulinic acid synthase 1
3β-HSD	3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase
CNS	central nervous system
CL	corpus luteum
FDX1	ferritin 1
FDXR	ferritin reductase
GST	glutathione S-transferases
LH	luteinizing hormone
LRH-1	liver receptor homolog 1
NR5A	nuclear receptor 5A
P450SCC	cytochrome P450 cholesterol side-chain lyase
rRNA	ribosomal RNA
SERBP1	serpine mRNA binding protein I
PGRMC1	progesterone receptor membrane component-1
PR	progesterone receptor
SF-1	steroidogenic factor 1
STAR	steroidogenic acute regulatory protein