Prostate-specific antigen

Last updated

KLK3
PSA KLK3 PDB 2ZCK.png
Available structures
PDB Ortholog search: M0QZF9 PDBe M0QZF9 RCSB
Identifiers
Aliases KLK3 , APS, KLK2A1, PSA, hK3, kallikrein related peptidase 3, Prostate Specific Antigen
External IDs OMIM: 176820; MGI: 97320; HomoloGene: 68141; GeneCards: KLK3; OMA:KLK3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

354

18048

Ensembl

ENSG00000142515

ENSMUSG00000066513

UniProt

P07288

P00757

RefSeq (mRNA)

NM_010915

RefSeq (protein)

NP_001025218
NP_001025219
NP_001639

NP_035045

Location (UCSC) Chr 19: 50.85 – 50.86 Mb Chr 7: 43.86 – 43.86 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Prostate-specific antigen (PSA), also known as gamma-seminoprotein or kallikrein-3 (KLK3), P-30 antigen, is a glycoprotein enzyme encoded in humans by the KLK3 gene. PSA is a member of the kallikrein-related peptidase family and is secreted by the epithelial cells of the prostate gland in men and the paraurethral glands in women. [5]

Contents

PSA is produced for the ejaculate, where it liquefies semen in the seminal coagulum and allows sperm to swim freely. [6] It is also believed to be instrumental in dissolving cervical mucus, allowing the entry of sperm into the uterus. [7]

PSA is present in small quantities in the serum of men with healthy prostates, but is often elevated in the presence of prostate cancer or other prostate disorders. [8] PSA is not uniquely an indicator of prostate cancer, but may also detect prostatitis or benign prostatic hyperplasia. [9]

Medical diagnostic uses

Prostate cancer

Screening

Clinical practice guidelines for prostate cancer screening vary and are controversial, in part due to uncertainty as to whether the benefits of screening ultimately outweigh the risks of overdiagnosis and overtreatment. [10] In the United States, the Food and Drug Administration (FDA) has approved the PSA test for annual screening of prostate cancer in men of age 50 and older.[ medical citation needed ] The patient is required to be informed of the risks and benefits of PSA testing prior to performing the test.[ medical citation needed ]

In the United Kingdom, the National Health Service (NHS) as of 2018 does not mandate, nor advise for PSA test, but allows patients to decide based on their doctor's advice. [11] The NHS does not offer general PSA screening, for similar reasons. [12]

PSA levels between 4 and 10 ng/mL (nanograms per milliliter) are considered to be suspicious, and consideration should be given to confirming the abnormal PSA with a repeat test. If indicated, prostate biopsy is performed to obtain a tissue sample for histopathological analysis. [ citation needed ]

While PSA testing may help 1 in 1,000 avoid death due to prostate cancer, 4 to 5 in 1,000 would die from prostate cancer after 10 years even with screening. This means that PSA screening may reduce mortality from prostate cancer by up to 25%. Expected harms include anxiety for 100 – 120 receiving false positives, biopsy pain, and other complications from biopsy for false positive tests.[ medical citation needed ]

Use of PSA screening tests is also controversial due to questionable test accuracy. The screening can present abnormal results even when a man does not have cancer (known as a false-positive result), or normal results even when a man does have cancer (known as a false-negative result). [13] False-positive test results can cause confusion and anxiety in men, and can lead to unnecessary prostate biopsies, a procedure which causes risk of pain, infection, and hemorrhage. False-negative results can give men a false sense of security, though they may actually have cancer.[ medical citation needed ]

Of those found to have prostate cancer, overtreatment is common because most cases of prostate cancer are not expected to cause any symptoms due to low rate of growth of the prostate tumor. Therefore, many will experience the side effects of treatment, such as for every 1000 men screened, 29 will experience erectile dysfunction, 18 will develop urinary incontinence, two will have serious cardiovascular events, one will develop pulmonary embolus or deep venous thrombosis, and one perioperative death.[ failed verification ] Since the expected harms relative to risk of death are perceived by patients as minimal, men found to have prostate cancer usually (up to 90% of cases) elect to receive treatment. [14] [15] [16]

Risk stratification and staging

Men with prostate cancer may be characterized as low, intermediate, or high risk for having/developing metastatic disease or dying of prostate cancer. PSA level is one of three variables on which the risk stratification is based; the others are the grade of prostate cancer (Gleason grading system) and the stage of cancer based on physical examination and imaging studies. D'Amico criteria for each risk category are: [17]

Low risk: PSA < 10, Gleason score ≤ 6, AND clinical stage ≤ T2a
Intermediate risk: PSA 10-20, Gleason score 7, OR clinical stage T2b/c
High risk: PSA > 20, Gleason score ≥ 8, OR clinical stage ≥ T3

Given the relative simplicity of the 1998 D'Amico criteria (above), other predictive models of risk stratification based on mathematical probability constructs exist or have been proposed to allow for better matching of treatment decisions with disease features. [18] Studies are being conducted into the incorporation of multiparametric MRI imaging results into nomograms that rely on PSA, Gleason grade, and tumor stage. [19]

Post-treatment monitoring

PSA levels are monitored periodically (e.g., every 6–36 months) after treatment for prostate cancer – more frequently in patients with high-risk disease, less frequently in patients with lower-risk disease. If surgical therapy (i.e., radical prostatectomy) is successful at removing all prostate tissue (and prostate cancer), PSA becomes undetectable within a few weeks. A subsequent rise in PSA level above 0.2 ng/mL [20] L[ disputed – discuss ] is generally regarded as evidence of recurrent prostate cancer after a radical prostatectomy; less commonly, it may simply indicate residual benign prostate tissue.[ citation needed ]

Following radiation therapy of any type for prostate cancer, some PSA levels might be detected, even when the treatment ultimately proves to be successful. This makes interpreting the relationship between PSA levels and recurrence/persistence of prostate cancer after radiation therapy more difficult. PSA levels may continue to decrease for several years after radiation therapy. The lowest level is referred to as the PSA nadir. A subsequent increase in PSA levels by 2.0 ng/mL[ disputed – discuss ] above the nadir is the currently accepted definition of prostate cancer recurrence after radiation therapy.[ citation needed ]

Recurrent prostate cancer detected by a rise in PSA levels after curative treatment is referred to as a "biochemical recurrence". The likelihood of developing recurrent prostate cancer after curative treatment is related to the pre-operative variables described in the preceding section (PSA level and grade/stage of cancer). Low-risk cancers are the least likely to recur, but they are also the least likely to have required treatment in the first place.[ citation needed ]

Prostatitis

PSA levels increase in the setting of prostate infection/inflammation (prostatitis), often markedly (> 100).

Forensic identification of semen

PSA was first identified by researchers attempting to find a substance in seminal fluid that would aid in the investigation of rape cases. [21] PSA is used to indicate the presence of semen in forensic serology. [22] The semen of adult males has PSA levels far in excess of those found in other tissues; therefore, a high level of PSA found in a sample is an indicator that semen may be present. Because PSA is a biomarker that is expressed independently of spermatozoa, it remains useful in identifying semen from vasectomized and azoospermic males. [23]

PSA can also be found at low levels in other body fluids, such as urine and breast milk, thus setting a high minimum threshold of interpretation to rule out false positive results and conclusively state that semen is present. [24] While traditional tests such as crossover electrophoresis have a sufficiently low sensitivity to detect only seminal PSA, newer diagnostics tests developed from clinical prostate cancer screening methods have lowered the threshold of detection down to 4 ng/mL. [25] This level of antigen has been shown to be present in the peripheral blood of males with prostate cancer, and rarely in female urine samples and breast milk. [24]

Sources

PSA is produced in the epithelial cells of the prostate, and can be demonstrated in biopsy samples or other histological specimens using immunohistochemistry. Disruption of this epithelium, for example in inflammation or benign prostatic hyperplasia, may lead to some diffusion of the antigen into the tissue around the epithelium, and is the cause of elevated blood levels of PSA in these conditions. [26]

More significantly, PSA remains present in prostate cells after they become malignant. Prostate cancer cells generally have variable or weak staining for PSA, due to the disruption of their normal functioning. Thus, individual prostate cancer cells produce less PSA than healthy cells; the raised serum levels in prostate cancer patients is due to the greatly increased number of such cells, not their individual activity. In most cases of prostate cancer, though, the cells remain positive for the antigen, which can then be used to identify metastasis. Since some high-grade prostate cancers may be entirely negative for PSA, however, histological analysis to identify such cases usually uses PSA in combination with other antibodies, such as prostatic acid phosphatase and CD57 . [26]

Mechanism of action

The physiological function of KLK3 is the dissolution of the coagulum, the sperm-entrapping gel composed of semenogelins and fibronectin. Its proteolytic action is effective in liquefying the coagulum so that the sperm can be liberated. The activity of PSA is well regulated. In the prostate, it is present as an inactive pro-form, which is activated through the action of KLK2, another kallikrein-related peptidase. In the prostate, zinc ion concentrations are 10 times higher than in other bodily fluids. Zinc ions have a strong inhibitory effect on the activity of PSA and on that of KLK2, so that PSA is totally inactive. [27]

Further regulation is achieved through pH variations. Although its activity is increased by higher pH, the inhibitory effect of zinc also increases. The pH of semen is slightly alkaline and the concentrations of zinc are high. On ejaculation, semen is exposed to the acidic pH of the vagina, due to the presence of lactic acid. In fertile couples, the final vaginal pH after coitus approaches the 6-7 levels, which coincides well with reduced zinc inhibition of PSA. At these pH levels, the reduced PSA activity is countered by a decrease in zinc inhibition. Thus, the coagulum is slowly liquefied, releasing the sperm in a well-regulated manner.[ citation needed ]

Biochemistry

Prostate-specific antigen (PSA, also known as kallikrein III, seminin, semenogelase, γ-seminoprotein and P-30 antigen) is a 34-kD glycoprotein produced almost exclusively by the prostate gland. It is a serine protease (EC 3.4.21.77) enzyme, the gene of which is located on the 19th chromosome (19q13) in humans. [28]

History

The discovery of prostate-specific antigen (PSA) is beset with controversy; as PSA is present in prostatic tissue and semen, it was independently discovered and given different names, thus adding to the controversy. [29]

Flocks was the first to experiment with antigens in the prostate [30] and 10 years later Ablin reported the presence of precipitation antigens in the prostate. [31]

In 1971, Mitsuwo Hara characterized a unique protein in the semen fluid, gamma-seminoprotein. Li and Beling, in 1973, isolated a protein, E1, from human semen in an attempt to find a novel method to achieve fertility control. [32] [33]

In 1978, Sensabaugh identified semen-specific protein p30, but proved that it was similar to E1 protein, and that prostate was the source. [34] In 1979, Wang purified a tissue-specific antigen from the prostate ('prostate antigen'). [35]

PSA was first measured quantitatively in the blood by Papsidero in 1980, [36] and Stamey carried out the initial work on the clinical use of PSA as a marker of prostate cancer. [29]

Serum levels

PSA is normally present in the blood at very low levels. The reference range of less than 4 ng/mL for the first commercial PSA test, the Hybritech Tandem-R PSA test released in February 1986, was based on a study that found 99% of 472 apparently healthy men had a total PSA level below 4 ng/mL. [37]

Increased levels of PSA may suggest the presence of prostate cancer. However, prostate cancer can also be present in the complete absence of an elevated PSA level, in which case the test result would be a false negative. [38]

Obesity has been reported to reduce serum PSA levels. [39] Delayed early detection may partially explain worse outcomes in obese men with early prostate cancer. [40] After treatment, higher BMI also correlates to higher risk of recurrence. [41]

PSA levels can be also increased by prostatitis, irritation, benign prostatic hyperplasia (BPH), and recent ejaculation, [42] [43] producing a false positive result. Digital rectal examination (DRE) has been shown in several studies [44] to produce an increase in PSA. However, the effect is clinically insignificant, since DRE causes the most substantial increases in patients with PSA levels already elevated over 4.0 ng/mL.

The "normal" reference ranges for prostate-specific antigen increase with age, as do the usual ranges in cancer, (per associated table). [45] [46]

Age40 - 4950 - 5960 - 6970-79years
CancerNo cancerCancerNo cancerCancerNo cancerCancerNo cancer
5th percentile 0.4 [45] 0.3 [45] 1.2 [45] 0.3 [45] 1.7 [45] 0.3 [45] 2.3 [45] 0.4 [45] ng/mL or μg/L
95th percentile
Non-African-American 		163.0 [45] 1.2 - 2.9 [46] 372.5 [45] 2.07 - 4.7 [46] 253.2 [45] 2.8 - 7.2613.2 [45] 4.0 - 9.0 [46]
95th percentile
African-American 		2.4 - 2.7 [46] 4.4 - 6.5 [46] 6.7 - 11 [46] 7.7 - 13 [46]

PSA velocity

Despite earlier findings, [47] recent research suggests that the rate of increase of PSA (e.g. >0.35 ng/mL/yr, the 'PSA velocity' [48] ) is not a more specific marker for prostate cancer than the serum level of PSA. [49]

However, the PSA rate of rise may have value in prostate cancer prognosis. Men with prostate cancer whose PSA level increased by more than 2.0 ng per milliliter during the year before the diagnosis of prostate cancer have a higher risk of death from prostate cancer despite undergoing radical prostatectomy. [50] PSA velocity (PSAV) was found in a 2008 study to be more useful than the PSA doubling time (PSA DT) to help identify those men with life-threatening disease before start of treatment. [51]

Men who are known to be at risk for prostate cancer, and who decide to plot their PSA values as a function of time (i.e., years), may choose to use a semi-log plot. An exponential growth in PSA values appears as a straight line [52] on a semi-log plot, so that a new PSA value significantly above the straight line signals a switch to a new and significantly higher growth rate, [52] i.e., a higher PSA velocity.

Free PSA

Risk of prostate cancer in two age groups based on Free PSA as % of Total PSA Free PSA bar graph.svg
Risk of prostate cancer in two age groups based on Free PSA as % of Total PSA

Most PSA in the blood is bound to serum proteins. A small amount is not protein-bound and is called 'free PSA'. In men with prostate cancer, the ratio of free (unbound) PSA to total PSA is decreased. The risk of cancer increases if the free to total ratio is less than 25%. (See graph) The lower the ratio is, the greater the probability of prostate cancer. Measuring the ratio of free to total PSA appears to be particularly promising for eliminating unnecessary biopsies in men with PSA levels between 4 and 10 ng/mL. [54] However, both total and free PSA increase immediately after ejaculation, returning slowly to baseline levels within 24 hours. [42]

Inactive PSA

The PSA test in 1994 failed to differentiate between prostate cancer and benign prostate hyperplasia (BPH) and the commercial assay kits for PSA did not provide correct PSA values. [55] Thus with the introduction of the ratio of free-to-total PSA, the reliability of the test has improved. Measuring the activity of the enzyme could add to the ratio of free-to-total PSA and further improve the diagnostic value of test. [56] Proteolytically active PSA has been shown to have an anti-angiogenic effect [57] and certain inactive subforms may be associated with prostate cancer, as shown by MAb 5D3D11, an antibody able to detect forms abundantly represented in sera from cancer patients. [58] The presence of inactive proenzyme forms of PSA is another potential indicator of disease. [59]

Complexed PSA

PSA exists in serum in the free (unbound) form and in a complex with alpha 1-antichymotrypsin; research has been conducted to see if measurements of complexed PSA are more specific and sensitive biomarkers for prostate cancer than other approaches. [60] [61]

PSA in other biologic fluids and tissues

Concentration of PSA in human body fluids
FluidPSA (ng/mL)
semen
200,000 - 5.5 million
amniotic fluid
0.60 - 8.98
breast milk
0.47 - 100
saliva
0
female urine
0.12 - 3.72
female serum
0.01 - 0.53

The term prostate-specific antigen is a misnomer: it is an antigen but is not specific to the prostate. Although present in large amounts in prostatic tissue and semen, it has been detected in other body fluids and tissues. [24]

In women, PSA is found in female ejaculate at concentrations roughly equal to that found in male semen. [5] Other than semen and female ejaculate, the greatest concentrations of PSA in biological fluids are detected in breast milk and amniotic fluid. Low concentrations of PSA have been identified in the urethral glands, endometrium, normal breast tissue and salivary gland tissue. PSA also is found in the serum of women with breast, lung, or uterine cancer and in some patients with renal cancer. [62]

Tissue samples can be stained for the presence of PSA in order to determine the origin of malignant cells that have metastasized. [63]

Interactions

Prostate-specific antigen has been shown to interact with protein C inhibitor. [64] [65] Prostate-specific antigen interacts with and activates the vascular endothelial growth factors VEGF-C and VEGF-D, which are involved in tumor angiogenesis and in the lymphatic metastasis of tumors. [66]

See also

Related Research Articles

<span class="mw-page-title-main">Prostate</span> Gland of the male reproductive system in most mammals

The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemically, and physiologically. Anatomically, the prostate is found below the bladder, with the urethra passing through it. It is described in gross anatomy as consisting of lobes and in microanatomy by zone. It is surrounded by an elastic, fibromuscular capsule and contains glandular tissue, as well as connective tissue.

<span class="mw-page-title-main">Prostate cancer</span> Male reproductive organ cancer

Prostate cancer is the uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Early prostate cancer causes no symptoms. Abnormal growth of prostate tissue is usually detected through screening tests, typically blood tests that check for prostate-specific antigen (PSA) levels. Those with high levels of PSA in their blood are at increased risk for developing prostate cancer. Diagnosis requires a biopsy of the prostate. If cancer is present, the pathologist assigns a Gleason score, and a higher score represents a more dangerous tumor. Medical imaging is performed to look for cancer that has spread outside the prostate. Based on the Gleason score, PSA levels, and imaging results, a cancer case is assigned a stage 1 to 4. A higher stage signifies a more advanced, more dangerous disease.

<span class="mw-page-title-main">Benign prostatic hyperplasia</span> Noncancerous increase in size of the prostate gland

Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss of bladder control. Complications can include urinary tract infections, bladder stones, and chronic kidney problems.

<span class="mw-page-title-main">Dihydrotestosterone</span> Human hormone

Dihydrotestosterone is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production of sebum and body hair composition.

<span class="mw-page-title-main">Dutasteride</span> Hormone replacement medication

Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of a benign prostatic hyperplasia (BPH), an enlarged prostate not associated with cancer. A few months may be required before benefits occur. It is also used for scalp hair loss in men and as a part of hormone therapy in transgender women. It is usually taken by mouth.

<span class="mw-page-title-main">Prostate biopsy</span> Medical test

Prostate biopsy is a procedure in which small hollow needle-core samples are removed from a man's prostate gland to be examined for the presence of prostate cancer. It is typically performed when the result from a PSA blood test is high. It may also be considered advisable after a digital rectal exam (DRE) finds possible abnormality. PSA screening is controversial as PSA may become elevated due to non-cancerous conditions such as benign prostatic hyperplasia (BPH), by infection, or by manipulation of the prostate during surgery or catheterization. Additionally many prostate cancers detected by screening develop so slowly that they would not cause problems during a man's lifetime, making the complications due to treatment unnecessary.

<span class="mw-page-title-main">Prostatic acid phosphatase</span> Human protein

Prostatic acid phosphatase (PAP), also prostatic specific acid phosphatase (PSAP), is an enzyme produced by the prostate. It may be found in increased amounts in men who have prostate cancer or other diseases.

Prostate cancer screening is the screening process used to detect undiagnosed prostate cancer in men without signs or symptoms. When abnormal prostate tissue or cancer is found early, it may be easier to treat and cure, but it is unclear if early detection reduces mortality rates.

Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known paralogue, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. These genes are localised to chromosome 19q13, forming the largest contiguous cluster of proteases within the human genome. Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation.

Early prostate cancer antigen-2 (EPCA-2) is a protein of which blood levels are elevated in prostate cancer. It appears to provide more accuracy in identifying early prostate cancer than the standard prostate cancer marker, PSA.

<span class="mw-page-title-main">KLK4</span> Mammalian protein found in Homo sapiens

Kallikrein-related peptidase 4 is a protein which in humans is encoded by the KLK4 gene.

Lower urinary tract symptoms (LUTS) refer to a group of clinical symptoms involving the bladder, urinary sphincter, urethra and, in men, the prostate. The term is more commonly applied to men – over 40% of older men are affected – but lower urinary tract symptoms also affect women. The condition is also termed prostatism in men, but LUTS is preferred.

<span class="mw-page-title-main">Prostate brachytherapy</span> Radiation therapy technique for the treatment of cancer

Brachytherapy is a type of radiotherapy, or radiation treatment, offered to certain cancer patients. There are two types of brachytherapy – high dose-rate (HDR) and low dose-rate (LDR). LDR brachytherapy is the one most commonly used to treat prostate cancer. It may be referred to as 'seed implantation' or it may be called 'pinhole surgery'.

<span class="mw-page-title-main">PCA3</span> Non-coding RNA in the species Homo sapiens

Prostate cancer antigen 3 is a gene that expresses a non-coding RNA. PCA3 is only expressed in human prostate tissue, and the gene is highly overexpressed in prostate cancer. Because of its restricted expression profile, the PCA3 RNA is useful as a tumor marker.

<span class="mw-page-title-main">Degarelix</span> Chemical compound

Degarelix, sold under the brand name Firmagon among others, is a hormonal therapy used in the treatment of prostate cancer.

<span class="mw-page-title-main">Cancer screening</span> Method to detect cancer

The objective of cancer screening is to detect cancer before symptoms appear, involving various methods such as blood tests, urine tests, DNA tests, and medical imaging. The purpose of screening is early cancer detection, to make the cancer easier to treat and extending life expectancy. In 2019, cancer was the second leading cause of death globally; more recent data is pending due to the COVID-19 pandemic.

Treatment for prostate cancer may involve active surveillance, surgery, radiation therapy – including brachytherapy and external-beam radiation therapy, proton therapy, high-intensity focused ultrasound (HIFU), cryosurgery, hormonal therapy, chemotherapy, or some combination. Treatments also extend to survivorship based interventions. These interventions are focused on five domains including: physical symptoms, psychological symptoms, surveillance, health promotion and care coordination. However, a published review has found only high levels of evidence for interventions that target physical and psychological symptom management and health promotion, with no reviews of interventions for either care coordination or surveillance. The favored treatment option depends on the stage of the disease, the Gleason score, and the PSA level. Other important factors include the man's age, his general health, and his feelings about potential treatments and their possible side-effects. Because all treatments can have significant side-effects, such as erectile dysfunction and urinary incontinence, treatment discussions often focus on balancing the goals of therapy with the risks of lifestyle alterations.

<span class="mw-page-title-main">Active surveillance of prostate cancer</span>

Active surveillance is a management option for localized prostate cancer that can be offered to appropriate patients who would also be candidates for aggressive local therapies, with the intent to intervene if the disease progresses. Active surveillance should not be confused with watchful waiting, another observational strategy for men that would not be candidates for curative therapy because of a limited life expectancy. Active surveillance offers men with a prostate cancer that is thought to have a low risk of causing harm in the absence of treatment, a chance to delay or avoid aggressive treatment and its associated side effects. While prostate cancer is the most common non-cutaneous cancer and second leading cause of cancer-related death in American men, it is conservatively estimated that approximately 100,000 men per year in the United States who would be eligible for conservative treatment through active surveillance, undergo unnecessary treatments. The management of localized prostate cancer is controversial and men with localized disease diagnosed today often undergo treatments with significant side effects that will not improve overall health outcomes. The 2011 NIH State-of-the-Science Conference Statement on the "Role of active surveillance in the management of men with localized prostate cancer" pointed out the many unanswered questions about observational strategies for prostate cancer that require further research and clarification. These included:

Andrew Julian Vickers is a biostatistician and attending research methodologist at Memorial Sloan Kettering Cancer Center. Since 2013, he has also been professor of public health at Weill Cornell Medical College. He is the statistical editor for the peer-reviewed journal European Urology.

<span class="mw-page-title-main">GTx-758</span> Chemical compound

GTx-758 is a synthetic nonsteroidal estrogen which was under development by GTx, Inc. for the treatment of advanced prostate cancer. As of 2016, it had completed two phase II clinical trials.

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