Introduction

Progesterone is an endogenous steroid hormone that is commonly produced by the adrenal cortex as well as the gonads, which consist of the ovaries and the testes. Progesterone is also secreted by the ovarian corpus luteum during the first ten weeks of pregnancy, followed by the placenta in the later phase of pregnancy. The conversion of progesterone generation from the corpus luteum to the placenta generally occurs after week ten.[1] The molecule progesterone is a derivative of cholesterol and has numerous functions in the human body, especially within the reproductive system.[2] This article seeks to review the function, physiology, clinical indications, and relevant information about progesterone. 

Issues of Concern

Issues of concern related to progesterone can lead to:

• Menstrual irregularities 
• Miscarriage and early labor 
• Decreased fertility 
• Granulosa cell tumor 
• Breast cancer [2]

Progesterone plays a vital role in the maintenance of the uterus during pregnancy. As such, an important issue of concern regarding the loss of this steroid hormone correlates with miscarriage and pre-term labor. One of the primary responsibilities of progesterone throughout pregnancy is to maintain a decreased level of vascular tone in the myometrium. Progesterone also influences the production of inflammatory mediators, such as human T-cells within the uterine cavity. Thus, a loss of progesterone leads to an increase in myometrial contractility coupled with a decrease in fighting off immunologic threats, ultimately leading to a higher risk of miscarriage and early delivery of the fetus.[3] Loss of progesterone is also associated with decreased fertility, increased endometrial hyperplasia, and subsequent risk of endometrial neoplasia. During the second phase of the menstrual cycle, the effects of progesterone result in the proliferation of the endothelial lining in the endometrium, resulting in a thickened endometrial wall. The result is an increased thickness and surface area of the endometrium in which implantation can occur. The pathogenesis behind infertility in the setting of low levels of progesterone is due to the loss of these necessary endometrial changes, resulting in an impaired ability of the endometrium to allow for proper implantation of a fertilized egg.[4] The loss of progesterone during the menstrual cycle also gives rise to the setting of unopposed estrogen on the uterus, which is a common risk factor for endometrial hyperplasia, potentially resulting in endometrial cancer. 

In contrast to deficiencies of progesterone, pathologies that pertain to excessive quantities of progesterone such as granulosa cell tumors and breast cancer are also areas of concern. The sex cord gives rise to granulosa cells, which regulate their effects through various signaling pathways. Granulosa cell tumors have shown to secrete high levels of estrogen and progesterone. These tumors also display high expression of estrogen and progesterone receptors.[5] Granulosa cell tumors are associated with Call-Exner bodies, which are granulosa cells that are visualized histologically and appear to represent a neoplastic process of basement membrane formation.[6] The effects of sex cord-stromal, such as granulosa cell tumors can lead to endometrial hyperplasia and post-menopausal bleeding.  

Cellular Level

Molecules of progesterone form from the process of steroidogenesis. While the biosynthetic pathway of producing progesterone completes in a manner that is independent of the steroid-producing organ, the specific subset and quantity of any given steroid hormone are dependent on the enzymatic expression of each respective organ. For example, while both the gonads and the ovaries perform steroidogenesis, these organs differ in their expression of specific enzymes, resulting in the production of unique and varied levels of hormones, such as progesterone. Progesterone, as with all steroids hormones, is derived from cholesterol and is uniquely composed of 21- carbon atoms. All such steroid hormones consist of a cyclopentane-perhydro-phenanthrene backbone, which has 17 carbon molecules that form four-rings.[7]

As a steroid hormone, progesterone functions by binding to a nuclear receptor located within the cytoplasm of a cell. Upon binding within the cytoplasm, progesterone will undergo dimerization followed by translocation to the nucleus, where it can bind to a strand of DNA. The binding of progesterone to DNA within the nucleus allows for the subsequent regulation of gene expression. This steroid hormone mainly binds to progesterone receptors (PGR) located throughout the body, commonly found as three isoforms of the progesterone receptors: PR-A, PR-B, and PR-C. There is an antagonistic relationship between the PR-A and PR-B receptors. PR-A can inhibit DNA transcription that is induced by PR-B as well as the estrogen receptor.[7] PR-A and PR-B are similar in composition except that PR-B has an additional 164 amino acids (it is also known as the AF-1), which gives PR-B a unique function. Although PR-A and B both share the AF-1 domain, it appears that the addition of AF-3 domain inhibits the AF-1 antagonist capabilities, allows for increased activity of PR-B. PR-C lacks both the AF-1 and DNA binding ability; however, it can still dimerize with other receptors and can bind to its ligand.[8]

Development

Progesterone plays a significant role during the normal menstruation cycle. The menstrual cycle is broadly divided into two sequential phases, beginning with the follicular phase, also known as the proliferative phase, and followed by the luteal phase. Each phase of menstruation requires a distinct set of hormones to allow for normal progression through a given cycle. The increase of progesterone, specifically in the menstrual cycle, occurs due to the initiation of a mid-cycle luteinizing hormone (LH) surge near the end of the follicular phase. This mid-cycle rise of progesterone also allows for an increase in follicle-stimulating hormone (FSH).[9] 

At the end of the LH and FSH surge, the menstrual cycle begins the luteal phase, during which progesterone prepares the endometrium in a woman’s uterus to receive and nourish the fertilized egg, also known as implantation during the luteal phase.[2] The increase in pulsatile progesterone causes capillary growth. Maturation of the capillaries allows them to permeate the granulosa layer of cells, causing a significant increase in vascularization in the endometrium and increased blood flow. If there is no implantation, progesterone levels decrease, causing sloughing of the endometrium, which leads to bleeding as a result of the coiling and constriction of spiral arterioles.[9][4]

However, if implantation does occur, then progesterone levels will remain elevated, resulting in the inhibition of endometrial sloughing and the subsequent transitioning into the role of pregnancy maintenance. During pregnancy, progesterone plays two key roles in inhibiting lactation and decreasing the ability of the myometrium to contract through metabolites which act via GABA receptors.[10] The reduction in uterine contraction by progesterone plays a significant function in assuring that implantation and development are occurring properly while simultaneously inhibiting premature expulsion of the fetus. After birth, progesterone levels drop, and the feedback inhibition on by progesterone is eliminated, thus promoting lactation.[2]

Organ Systems Involved

In addition to maintenance of the endometrium during pregnancy and vascularization of the endometrium during ovulation, progesterone also plays a role in bone formation. The process of resorption and building of new bone requires hormones such as estradiol and progesterone, as well as bone-forming cells, such as osteoblasts. Progesterone increases the process of bone formation by stimulating P-4-receptor mediated osteoblastic growth during the initiation of bone modeling.[11] This process of formation is a balance between estradiol, which rapidly resorbs bone and progesterone, which slowly forms bone. In turn, the findings of ovulatory abnormalities due to deficiencies of progesterone result in low levels of P4 and a subsequent decline in the ability to achieve peak bone mineral density. 

Progesterone additionally plays a crucial element in the hypothalamic-pituitary-adrenocortical axis. During the luteal phase, the hypothalamus releases gonadotropin-releasing hormone (GnRH), which acts on a gland called the anterior pituitary. In response to this release of GnRH, the anterior pituitary will release FSH and LH, which will subsequently act on the gonads. In the female ovary, this release of FSH and LH on the gonads causes the release of progesterone. Excess amounts of progesterone will cause negative feedback inhibition on each prior organ, resulting in the cessation of the release of hormones. This process allows for regulated control of hormone levels. Abnormalities of this axis results in dysregulation of hormone levels affecting numerous organ systems and downstream hormones within the body. 

Although progesterone is primarily associated with the reproductive system, it also plays a functional role in the neuroendocrine axis. Progesterone may demonstrate neuroprotective factors in both the central as well as the peripheral nervous system, affecting myelination processes and regulation of astroglial plasticity. Additionally, progesterone functions to aid neuron survival in the setting of neurodegenerative diseases, such as amyotrophic lateral sclerosis. These effects are due to the expression of progesterone receptors located throughout the nervous system.[12]  

Function

Progesterone is primarily known as the pregnancy hormone in females, and most of its function relates to maintaining pregnancy specifically by preparing the endometrium, decreasing myometrial contractions for implantation, promoting gestation, and inhibition of lactation during pregnancy.[2] It also plays a role in the menstrual cycle, causing capillary growth and development with the result of increased vascularization and blood flow. Progesterone additionally causes an increase in the mucous lining of the cervix, resulting in a barrier of inhibition for sperm to penetrate through. The properties of increased mucus secretion of progesterone provide a clinically relevant utilization for progestin-dependent contraceptives. The mucosal thickening in the cervix by progesterone also plays an important role in innate immunity by establishing a barrier to threatening infections and secreting immune cells such as leukocytes.[13] In males, progesterone functions to facilitate spermiogenesis and androgen synthesis.[2]

Progesterone has also been studied regarding its protective effect on various neurological disorders, osteoporosis, benign prostate hyperplasia, and osteoporosis.[14] In the setting of the nervous system, progesterone plays a role in myelin proliferation, whereas in the musculoskeletal system, this steroid hormone interacts with estrogen to form an equilibrium for peak bone mineral density. The link between progesterone receptors and benign prostate hyperplasia has support from the expression of progesterone receptors in the prostate. 

Mechanism

Progesterone is a steroid hormone; thus, its mechanism is very similar to the body’s other steroid hormones, such as estrogen and glucocorticoids, which utilize intracellular receptors for their method of action. Due to the lipophilic nature of progesterone, it can readily cross the membrane of a target cell and bind to and activate progesterone receptors located within the cytoplasm. This progesterone and receptor complex then transports to the nucleus and binds to DNA, specifically near the promoter regions of genes that contain enhancers, containing hormone response elements. This binding of the complex to the promoter can either enhance or repress transcription, which ultimately alters the production of proteins.[12]

Related Testing

Almost always, women who are experiencing early pregnancy problems, such as vaginal bleeding or abdominal pain, will come to the clinic to receive a consultation. The clinician may administer a progesterone test, and progesterone levels could be indicative of numerous things.[15] Low progesterone levels, specifically, can indicate a significant problem because deficiency of this hormone commonly correlates with miscarriages or ectopic pregnancies. High progesterone is usually indicative of a successful pregnancy, and could further indicate that ovulation has occurred.[15][16] 

To ensure ovulation has occurred, progesterone can be measured in the serum, or its metabolite can be measured in urine. A serum progesterone level of >3 ng/ml in the luteal phase indicates that ovulation has occurred.[16]

Finally, another test completed with progesterone is called the progestin-challenge test. In this test, exogenous progesterone (such as medroxyprogesterone) is administered to the patient. The progesterone is then stopped, and in normal conditions, withdrawal bleeding should occur. However, if withdrawal bleeding does not occur, three possible causes could be at the root: there is not enough estrogen to allow the endometrium to grow, the endometrium has suffered an injury, or the outflow of the blood is blocked.[17]

Pathophysiology

Breast Cancer

Breast cancer often categorizes as either estrogen-receptor-positive (ER+) or progesterone-receptor positive (PR+) or ER+/PR+. The effects of progesterone, as well as estrogen, within the breast tissue, is closely related to mammary gland growth. As such, the upregulation of these receptors within the breast tissue can increase cell proliferation in the mammary gland by increasing the number of breast cells in the G2/M phase resulting in an elevated risk of developing breast cancer.[18] Progesterone also plays a role in increasing levels of molecules that are significant in signaling transduction pathways such as EGFR, further elevating the risk of developing breast cancer due to the sensitization of these proliferative processes.[19] 

Ovarian Cancer

Progesterone can have both a protective or a proliferative effect on ovarian cells. In terms of ovarian neoplasia, the level of progesterone is indirectly related, such that the higher the level of progesterone, the lower the risk of developing ovarian cancer. Instances such as pregnancy, the use of oral contraceptives, and breastfeeding are all linked to increased levels of progesterone and a decreased risk of ovarian cancer. Conversely, advanced age, earlier onset of menstruation, and anovulatory cycles are associated with an increased risk of developing ovarian cancer due to their low levels of progesterone. Progesterone receptor expression also plays a role in the development of ovarian cancer. The expression of progesterone receptor B (PR-B) is associated with ovarian cancer to a greater extent than progesterone receptor A PR-A. PR-B acts via a transcriptional factor known as FOXO1, which goes on to induce p21.[20]

Clinical Significance

Progesterone can be useful for the identification of various clinical complications and diagnoses. Often, progesterone is combined with estrogen to be used as a contraceptive and regulate pregnancy timing or induce withdrawal bleeding.[8][21][8] It also can be used to treat secondary amenorrhea, anovulation, and endometrial hyperplasia. Dysfunction vaginal bleeding, especially occurring in adolescents or postmenopausal women, can often be treated by progesterone administration.[21] These indications are related to the reproductive effects of progesterone; however, progesterone can be used for non-reproductive applications too. For example, clinicians have used it to treat hypertension and COPD. Additionally, there are citations of its use to treat drug dependence also, specifically cocaine and nicotine.[2][21]

Chronic use of progesterone clinically can cause one or many adverse effects. Some common side effects include[21]: 

• Abdominal cramps 
• Back pain 
• Breast tenderness 
• Hypotension and dizziness
• Hypercoagulant state 
• Vaginal bleeding