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 ]


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 ]


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 ]


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 ]


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


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 ]


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 ]


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 ]


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 ]


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 ]


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 ] [ 38 ] [ 39 ] [ 40 ] [ 41 ] [ 42 ] [ 43 ] [ 44 ]


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 . [ 45 ]


Obesity  has been reported to reduce serum PSA levels. [ 46 ]  Delayed early detection may partially explain worse outcomes in obese men with early prostate cancer. [ 47 ]  After treatment, higher BMI also correlates to higher risk of recurrence. [ 48 ]


PSA levels can be also increased by  prostatitis , irritation,  benign prostatic hyperplasia  (BPH), and recent ejaculation, [ 49 ] [ 50 ]  producing a  false positive  result. Digital  rectal examination  (DRE) has been shown in several studies [ 51 ] [ 52 ] [ 53 ] [ 54 ]  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. PSA levels are higher during the summer than during the rest of the year. [ 55 ] [ 56 ]


The "normal"  reference ranges  for prostate-specific antigen increase with age, as do the usual ranges in cancer (per associated table). [ 57 ] [ 58 ]


Despite earlier findings, [ 59 ]  recent research suggests that the rate of increase of PSA (e.g. >0.35   ng/mL/yr, the 'PSA velocity' [ 60 ] ) is not a more specific marker for prostate cancer than the serum level of PSA. [ 61 ]


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 . [ 62 ]  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. [ 63 ]


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 [ 64 ]  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, [ 64 ]  i.e., a higher PSA velocity.


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. [ 66 ]  However, both total and free PSA increase immediately after ejaculation, returning slowly to baseline levels within 24 hours. [ 49 ]


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. [ 67 ]  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. [ 68 ]  Proteolytically active PSA has been shown to have an anti-angiogenic effect  [ 69 ]  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. [ 70 ]
The presence of inactive proenzyme forms of PSA is another potential indicator of disease. [ 71 ]


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. [ 72 ] [ 73 ]


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. [ 74 ]


Tissue samples can be stained for the presence of PSA in order to determine the origin of malignant cells that have metastasized. [ 75 ]


Prostate-specific antigen has been shown to  interact  with  protein C inhibitor . [ 76 ] [ 77 ]
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. [ 78 ]


Schiller–Duval body  is a cellular structure seen by  microscope  in  endodermal sinus tumors  (yolk sac tumors) which are the most common testicular cancer in children. Schiller-Duval bodies are present in approximately 50% of these tumors, and if found are  pathognomonic . [ 1 ]  They are named for  Mathias-Marie Duval  and  Walter Schiller [ 2 ]  who described them in the late nineteenth century. [ 3 ]


Schiller–Duval bodies are said to resemble a  glomerulus . [ 4 ]  They have a  mesodermal  core with a central  capillary , all lined by flattened layers of both visceral and parietal cells.  Immunofluorescent  stain may show eosinophilic  hyalin -like globules both inside and outside the  cytoplasm  that contain  AFP  and  alpha 1-antitrypsin .


Sexual health clinics  specialize in the prevention and treatment of  sexually transmitted infections .


Sexual health clinics are also called  sexually transmitted disease  (STD) clinics ,  sexually transmitted infection (STI) clinics ,  venereal disease (VD) clinics , or  genitourinary medicine  (GUM) clinics . [ citation needed ]


Sexual health clinics differ from  reproductive health  and  family planning  clinics. Sexual health clinics offer only some reproductive health services. Reproductive health clinics, such as  Planned Parenthood , offer most of the services of sexual health clinics. [ citation needed ]


Sexual health clinics provide some or all of the following: [ citation needed ]


Many clinics provide vaccinations to prevent  infections  from the  hepatitis A  and  B   viruses . [ 1 ]
Young women may receive vaccinations to prevent infection from some strains of the  human papillomavirus  (HPV). [ citation needed ]


Many clinics provide  interpreting  for the hearing impaired or speakers of other languages. [ citation needed ]


Many clinics will help patients tell their sexual contacts if they have a sexually transmitted infection, anonymously if needed. [ 2 ]


Public governmental and  non-profit  clinics often provide services for free or adjust the fee based on a patient's ability to pay.
Sexual health clinics often offer services without appointments. Some clinics open evenings or weekends. Some clinics have separate hours or facilities for men and women. Some clinics serve only specific populations such as women, men,  MSM ,  youths ,  LGBT , ethnic groups, the poor, or students. [ citation needed ]


With the patient's  consent , a  clinician  will inspect the patient visually and by touch. If needed, the clinician will take samples to  test  for  sexually transmitted infections . [ citation needed ]


In a private room or space, the patient will partially undress. [ citation needed ]


The clinician may inspect the patient's: [ citation needed ]


The clinician may swab the patient's:


The clinician may take small blood samples by  pricking a finger  or from a  vein [ 4 ]  to test for  HIV ,  syphilis , and possibly  herpes [ 5 ]  and  hepatitis C . [ 6 ] [ 7 ] [ 8 ]


The clinician may ask for a small  urine  sample, given in private, to test for  chlamydia  and possibly  gonorrhea .
The inspections and taking samples do not hurt, but swabbing the urethra and cervix, and a finger prick blood sample feel uncomfortable.
Women will often receive a  pelvic exam , both external and internal, but usually less thorough than a reproductive health exam.
A patient can choose a female or male clinician if available.
A patient can have a  chaperone .
Some clinics have separate hours or facilities for men and women. [ citation needed ]


Medical  confidentiality  is an important part of the  medical ethics  of a  doctor–patient relationship . Sexual health clinics follow local standards of medical confidentiality to protect the privacy of patients. Some clinics provide anonymous services or protect confidentiality by having a patient use a number or a pseudonym. [ 9 ]


Additional privacy protections sometimes apply to matters of sexuality and reproduction, since these areas are sensitive in many cultures. The  diagnosis of HIV/AIDS  has legal restrictions in patient confidentiality, and some clinics use  rapid antibody tests  to provide results to a patient within 30 minutes, without holding the patient's records. [ citation needed ]


In the United States, clinics receiving federal funding from  Medicaid  or  Title X  of the  Public Health Service Act  must treat all patients confidentially. Thus minors can receive services without parental notification or consent. [ 10 ] [ 11 ] [ 12 ]  Additionally, medical records for all patients age 18 and above are strictly confidential under  HIPAA . [ 13 ]


Medical standards of  informed consent  apply to sexual health clinics. A patient needs information about the purposes and consequences of examinations, tests, treatments, and other procedures. A patient may then choose whether to consent to these procedures. [ citation needed ]


A  minor  may consent to receive some or all of the procedures at many sexual health clinics. [ citation needed ]


Sperm motility  describes the ability of  sperm  to move properly through the female reproductive tract ( internal fertilization ) or through water ( external fertilization ) to reach the  egg . Sperm motility can also be thought of as the  quality , which is a factor in successful  conception ; sperm that do not "swim" properly will not reach the egg in order to  fertilize  it. Sperm motility in mammals also facilitates the passage of the sperm through the  cumulus oophorus  (a layer of cells) and the  zona pellucida  (a layer of  extracellular matrix ), which surround the mammalian  oocyte .


In the wood mouse  Apodemus sylvaticus , sperms aggregate in 'trains' that are better able to fertilize eggs because they are more capable of navigating the viscous environment of the female reproductive tract. The trains move in a sinusoidal motion.


Sperm motility is also affected by certain factors released by eggs. [ 1 ]


Sperm movement is activated by changes in intracellular ion concentration. [ 2 ]  The changes in ion concentration that provoke motility are different among species. In  marine invertebrates  and  sea urchins , the rise in pH to about 7.2–7.6 activates  ATPase  which leads to a decrease in intracellular potassium, and thus induces membrane  hyperpolarization . As a result, sperm movement is activated. [ 3 ]  The change in cell volume which alters intracellular ion concentration can also contribute to the activation of sperm motility. In some  mammals , sperm motility is activated by increase in pH, calcium ion and  cAMP , yet it is suppressed by low pH in the  epididymis .


The tail of the sperm - the  flagellum  - confers motility upon the sperm, and has three principal components:


Back and forth movement of the tail results from a rhythmical longitudinal sliding motion between the anterior and posterior tubules that make up the axoneme. The energy for this process is supplied by  ATP  produced by mitochondria. The velocity of a sperm in fluid medium is usually 1–4 mm/min. This allows the sperm to move towards an  ovum  in order to fertilize it.


The axoneme is attached at its base to a  centriole  known as the distal centriole and acts as a  basal body . [ 4 ]  In most animals, this distal centriole act as a shock absorber preventing the  microtubules  filaments from moving at the axoneme base. In contrast, in mammals, the distal centriole evolved an atypical structure, known as the atypical distal centriole. [ 5 ]  The atypical centriole is made of splayed  microtubules  organized into left and right sides. During sperm movement, the two sides move relative to each other, helping to shape the waveform of the sperm tail. [ 5 ]


In mammals,  spermatozoa  mature functionally through a process which is known as  capacitation . When spermatozoa reach the isthmic  oviduct , their motility has been reported to be reduced as they attach to epithelium. Near the time of ovulation, hyperactivation occurs. During this process, the flagella move with high curvature and long wavelength. [ 6 ]  Hyperactivation is initiated by extracellular calcium; however, the factors that regulate calcium level is unknown. [ 7 ]


Without technological intervention, a non-motile or abnormally-motile sperm is not going to fertilize. Therefore, the fraction of a sperm population that is motile is widely used as a measure of semen quality . Insufficient sperm motility is a common cause of  subfertility  or  infertility . Several measures are available to improve sperm quality.


Sperm motility is dependent on several metabolic pathways and regulatory mechanisms.


The axonemal bend movement is based on the active sliding of axonemal doublet microtubules by the molecular motor dynein, which is divided into an outer and an inner arm. Outer and inner arm plays different roles in the production and regulation of flagellar motility: the outer arm increase the beat frequency, the inner arm is involved in the propulsion and propagation of flagellar bending. The bending of the flagellum is due to subsequent cycles of dynein arm attachment, generation of force and detachment on the B subunit. The binding of the axoneme is the result of the presence of a resistance to the microtubule sliding generated by dynein.


Dyneins on the two sides of the central pair apparatus are regulated in an opposite way by an activation/disactivation game made by the radialspoke-central pair apparatus, that regulates the flagellar bending. Sperm motility is regulated by several pathways and the most important are the Calcium pathway and the PKA pathway. This pathwaysinvolve ions, adenylyl cyclase, cAMP, membrane channels and phosphorylations.


The first event is the activation of a  Na + /HCO3  −   (NBC) co-transporter and the regulation of HCO3  −  /Cl −  by SLC26 transporters, that bring to an increase in HCO3  −  levels.


The second event is the activation of an  Na + /H +  exchanger and of the proton channel Hv-1, that leads to an increase in pH levels.


These increase in HCO3  −  and pH levels bring to the activation of the CatSper channel, a sperm membrane specific calcium channel. CatSperm can be activated also by progesterone and albumine. CatSper, once activated, opens and let free calcium entrance inside the cell, with a global increase in calcium intracellular levels.


Together, the increase in HCO3  −  , pH and calcium leads to the activation of a soluble adenylyl cyclase (SAC or SACY), that increases the production of cAMP and brings to the activation of PKA, a protein kinase that phosphorylates several tyrosine kinases and leads to a phosphorylation cascade that ends with the phosphorylation of the axonemal dynein and the start of flagellar movement. [ 8 ]


Sperm  DNA damage  is common in  infertile men . [ 9 ]   About 31% of men with sperm motility defects have high levels of sperm  DNA fragmentation . [ 10 ]


Sperm motility increases from puberty through one's mid-thirties. Research shows that from the age of 36 onwards, sperm motility decreases from 40% Grade A & B to 31% in one's 50s. The effects of aging on semen quality is summarized below based on a study of 1,219 subjects: [ 11 ]


[Min-Max]


The  spermatid  is the  haploid  male  gametid  that results from division of secondary  spermatocytes .  As a result of  meiosis , each spermatid contains only half of the genetic material present in the original primary spermatocyte.


Spermatids are connected by cytoplasmic material and have superfluous cytoplasmic material around their nuclei.


When formed,  early round spermatids  must undergo further maturational events to develop into  spermatozoa , a process termed  spermiogenesis  (also termed  spermeteliosis ).


The spermatids begin to grow a living thread, develop a thickened mid-piece where the  mitochondria  become localised, and form an  acrosome .  Spermatid DNA also undergoes packaging, becoming highly condensed.  The DNA is packaged firstly with specific nuclear basic proteins, which are subsequently replaced with  protamines  during spermatid elongation.  The resultant tightly packed  chromatin  is transcriptionally inactive.


In 2016 scientists at  Nanjing Medical University  claimed they had produced cells resembling mouse spermatids artificially from  stem cells .  They injected these spermatids into mouse eggs and produced pups. [ 1 ]


During spermatid  haploid   genome  remodeling, the majority of  histones  are replaced by  protamines , and the  DNA  is compacted. During this compaction, transient single- and double-strand breaks are introduced into the sperm DNA. [ 2 ]   The conventional  non-homologous end joining  pathway for repairing double-strand breaks is not available for elongated spermatids. However, spermatids can carry out limited repair of exogenous and programmed double-strand breaks using an alternative error-prone non-homologous end joining repair pathway. [ 3 ]  If DNA strand breaks persist in mature sperm, the result can be increased sperm DNA fragmentation which is associated with impaired fertility and an increased incidence of miscarriage. [ 4 ]


As postmeiotic  germ cells  develop to mature  sperm  they progressively lose the ability to repair  DNA damage  that may then accumulate and be transmitted to the  zygote  and ultimately the embryo. [ 5 ]   In particular, the  repair of DNA  double-strand breaks by the  non-homologous end joining  pathway, although present in round spermatids, appears to be lost as they develop into elongated spermatids. [ 6 ]


Testicular Immunology is the study of the  immune system  within the  testis . It includes an investigation of the effects of  infection ,  inflammation  and immune factors on testicular function. Two unique characteristics of  testicular immunology  are evident: (1) the testis is described as an  immunologically privileged site , where suppression of immune responses occurs; and, (2) some factors which normally lead to inflammation are present at high levels in the testis, where they regulate the development of  sperm   instead of promoting inflammation.


Immune cells of the human testis are not as well characterized as those from rodents, due to the rarity of normal human testes available for experiment. The majority of experiments have studied the rat testis due to its convenience: it is of relatively large size and is easily extracted from experimental animals.


Macrophages  are directly involved in the fight against invading micro-organisms as well as being  antigen-presenting cells  which activate  lymphocytes . Early studies demonstrated the presence of macrophages in the rat testis  [ 5 ]   Testicular macrophages are the largest population of immune cells in the rodent testis. [ 6 ] [ 7 ]  Macrophages have also been found in the testes of humans, [ 8 ]  guinea pigs, hamsters, [ 9 ]  boars, [ 10 ]  horses  [ 11 ]  and bulls. [ 12 ]  They originate from blood  monocytes  which move into the testis then mature into macrophages. In the rat, testicular macrophages have been described as either “resident” or “newly arrived” from the blood supply. [ 13 ] [ 14 ]   It is likely that most of the adult population of testicular macrophages in adult rats are a result of very rapid proliferation of early precursors that entered the testis during postnatal maturation [ 15 ]


Testicular macrophages can respond to infectious stimuli and become activated (undergo changes enabling the killing of the invading micro-organism), but do so to a lesser extent than other types of macrophages. [ 16 ] [ 17 ]  An example is production of the inflammatory cytokines  TNFα  and  IL-1 β by activated rat testicular macrophages: these macrophages produce significantly less TNFα and IL-1β than activated rat peritoneal macrophages. [ 17 ] [ 18 ]  Aside from responding to infectious stimuli, testicular macrophages are also involved in maintaining normal testis function.  They have been shown to secrete 25-hydroxycholesterol, a sterol that can be converted to testosterone by Leydig cells. [ 19 ]  Their presence is necessary for the normal development and function of the  Leydig cells , [ 20 ] [ 21 ] [ 22 ]  which are the testosterone-producing cells of the testis.


B-lymphocytes  take part in the  adaptive immune response  and produce antibodies. These cells are not normally found in the testis, even during inflammatory conditions. The lack of B-lymphocytes in the testis is significant, since these are the antibody-producing cells of the immune system. Since anti-sperm antibodies can cause infertility, it is important that antibody-producing B-lymphocytes are kept separated from the testis.


T-lymphocytes  (T-cells) are white blood cells which take part in cell-mediated immunity. They are often found within tissues where they can be activated by antigen-presenting cells upon infection. They are present in rat  [ 23 ] [ 24 ]  and human testes, [ 25 ]  where they constitute approximately 10 to 20% of the immune cells present, as well as mouse  [ 26 ]  and ram  [ 24 ]  testes. Both  cytotoxic T-cells  and  Helper T cells  are found in the testes of rats. [ 27 ]  Also present in the testes of rats and humans are  natural killer cells [ 1 ] [ 27 ]  and  Natural killer T cells  have been found in rats and mice.


Mast cells  are regulators of immune responses, particularly those against  parasites . They are also involved in the development of  autoimmune diseases  and  allergies . Mast cells have been found in relatively low numbers in the testes of humans, rats, mice, dogs, cats, bulls, boars and deer. [ 28 ] [ 29 ]  In the mammalian testis mast cells regulate testosterone production. [ 29 ]  There are two lines of evidence that restriction of mast cell activation in the testis could be beneficial during treatment of inflammatory conditions; (1) In experimental models of testicular inflammation, mast cells were present in 10-fold greater numbers and showed signs of activation, [ 30 ]  and (2) Treatment with drugs which stabilize mast cell activation has proved beneficial in treating some types of male infertility. [ 31 ] [ 32 ] [ 33 ]


Eosinophils  directly fight parasitic infections and are involved in allergic reactions. They have been found in relatively low numbers in the rat, mouse, dog, cat, bull and deer testes. [ 28 ]  Almost nothing is known about their significance or function in the testis.


Dendritic cells  initiate  adaptive immune responses . Relatively small amounts of dendritic cells have been found in the testes of humans, [ 34 ]  rats  [ 35 ]  and mice. [ 36 ] [ 37 ]  The functional role of dendritic cells in the testis is not well understood, although they have been shown to be involved in  autoimmune   orchitis  during animal experiments. [ 28 ] [ 35 ]  When autoimmune orchitis is induced in rats, the dendritic cell population of the testis greatly increases. [ 35 ]  This is likely to contribute to testicular inflammation, considering the well-established role of dendritic cells in other types of autoimmune inflammation. [ 38 ]


Neutrophils  are white blood cells which are present in the blood but not normally in tissues. They move out from the blood into tissues and organs upon infection or damage. They directly fight invading pathogens such as bacteria. Neutrophils are not found in the rodent testis under normal conditions but can enter from the blood supply upon infection or inflammatory stimulus. This has been demonstrated in the rat after injection with bacterial cell wall components to produce an immune reaction. [ 39 ]  Neutrophils also enter the rat testis after treatment with hormones that increase the permeability of blood vessels. [ 40 ]  In humans, neutrophils have been found in the testis when associated with some tumors. [ 41 ]  In rat experiments,  testicular torsion  leads to neutrophil entry into the testis. [ 42 ]  Neutrophil activity in the testis is an inflammatory response which needs to be tightly regulated by the body, since inflammation-induced damage to the testis can lead to infertility. [ 43 ] [ 44 ]  It is assumed that the role of the immunosuppressive environment of the testis is to protect developing sperm from inflammation.


Sperm are immunogenic - that is they will cause an autoimmune reaction if transplanted from the testis into a different part of the body. This has been demonstrated in experiments using rats by Landsteiner (1899) and Metchinikoff (1900), [ 1 ] [ 29 ]  mice  [ 45 ]  and guinea pigs. [ 46 ]  The likely reason for this is that sperm first mature at puberty, after  immune tolerance  is established, therefore the body recognizes them as foreign and mounts an immune reaction against them. Therefore, mechanisms for their protection must exist in this organ to prevent any autoimmune reaction. The  blood-testis barrier  is likely to contribute to the survival of sperm. However, it is believed in the field of testicular immunology that the blood-testis barrier cannot account for all immune suppression in the testis, due to (1) its incompleteness at a region called the  rete testis [ 29 ]  and (2) the presence of immunogenic molecules outside the blood-testis barrier, on the surface of  spermatogonia . [ 1 ] [ 29 ]   Another mechanism which is likely to protect sperm is the suppression of immune responses in the testis. [ 17 ] [ 47 ]  Both the suppression of immune responses and the increased survival of grafts in the testis have led to its recognition as an  immunologically privileged site . Other immunologically privileged sites include the eye, brain and uterus. [ 48 ]


The two main features of immune privilege in the rat testis are;


It is also predicted that the high level of inflammatory  cytokines  in the testis contributes to immune privilege. [ 29 ]


The existence of immune privilege in the testes of rodents is well accepted, due to many experiments demonstrating prolonged, and sometimes indefinite, survival of tissue transplanted into the testis, [ 49 ] [ 50 ]  or testicular tissue transplanted elsewhere. [ 51 ] [ 52 ]  Evidence includes the tolerance of testicular grafts in mice and rats, as well as the increased survival of transplants of pancreatic insulin-producing cells in rats, when cells from the testes ( Sertoli cells ) are added to the transplanted material. [ 53 ]  Complete  spermatogenesis , forming functional pig or goat sperm, can be established by the grafting of pig or goat testicular tissue onto the backs of mice - however, immunodeficient mice needed to be used. [ 51 ]


The presence of immune-privilege in the human testis is controversial and insufficient evidence exists to either confirm or rule out this phenomenon.


Sperm are protected from autoimmune attack, which when it occurs in humans leads to infertility. [ 54 ]  Local injury of  seminiferous tubules  caused by fine-needle biopsies in humans does not cause testicular inflammation ( orchitis ). [ 55 ]  Furthermore, human testis cells tolerate early  HIV  infection with little response. [ 56 ]


In transplant experiments, primate testes fail to support grafts of monkey thyroid tissue. [ 57 ]  Human testis tissue transplanted into the mouse elicited an immune response and was rejected, however, this immune response was not as extensive as that against other types of grafted tissue. [ 58 ]


How the testicular environment suppresses the immune response is only partially understood. Recent experiments have uncovered a number of biological processes that most likely contribute to immune privilege in the testes of rodents:


Since protection of developing sperm is so important to the survival of a species, it would not be surprising if more than one mechanism were in use.


Curiously, the testis contains factors such as  cytokines , which are usually only produced upon infections and tissue damage. The cytokines interleukin-1α ( IL-1 α),  IL-6  and  Activin  A are found in the testis, often at high levels. [ 62 ] [ 63 ] [ 64 ] [ 65 ] [ 66 ]  In other tissues, these cytokine would promote inflammation, but here they control testis function. They regulate the development of sperm by controlling their cell division and survival. [ 67 ] [ 68 ] [ 69 ] [ 70 ] [ 71 ]


Other immune factors found in the testis include the enzyme inducible  nitric oxide synthase  (iNOS), and its product  nitric oxide  (NO), [ 72 ] [ 73 ] [ 74 ]   transforming growth factor beta  (TGFβ), [ 75 ]  the enzyme  cyclooxygenase -2 (COX-2) and its product  prostaglandin E2 , [ 76 ]  and many others. Further research is required to define the functional roles of these immune factors in the testis.


Mumps  is a viral disease which causes swelling of the salivary glands and testes. The mumps virus lives in the upper respiratory tract and spreads through direct contact with saliva. [ 77 ]  Prior to widespread vaccination programs, it was a common childhood disease. Mumps is generally not serious in children, but in adults, where sperm have matured in the testis, it can cause more severe complications, such as infertility.


Gonorrhea  is a sexually transmitted disease caused by the bacteria  Niesseria gonorrhea  which can lead to testicular pain and swelling. Gonorrhea also infects the female reproductive system around the cervix and uterus, and can grow in the mouth, throat, eyes and anus. [ 78 ]  It can be effectively treated with antibiotics, however, if untreated, gonorrhea can cause infertility in men.  Chlamydia  is caused by the sexually transmitted bacteria  Chlamydia trachomatis  which infects the genitals. It more commonly affects women, and if untreated, can lead to  pelvic inflammatory disease  and infertility. [ 79 ]  Serious symptoms in men are rare, but include swollen testicles and an unusual discharge from the penis. It is effectively treated with antibiotics.


Antisperm antibodies  (ASA) have been considered as infertility cause in around 10–30% of infertile couples. [ 80 ]   ASA production are directed against surface antigens on sperm, which can interfere with sperm motility and transport through the female reproductive tract, inhibiting capacitation and  acrosome reaction , impaired  fertilization , influence on the implantation process, and impaired growth and development of the  embryo . Risk factors for the formation of antisperm antibodies in men include the breakdown of the blood‑testis barrier, trauma and surgery, orchitis,  varicocele , infections,  prostatitis ,  testicular cancer , failure of immunosuppression and unprotected receptive anal or oral sex with men. [ 80 ] [ 81 ]


Testicular torsion  is a condition of physical twisting of the testis which results in cutting off the blood supply. It leads to damage that, if not treated within a few hours, causes the death of testicular tissue, and requires removal of the testis to prevent  gangrene , and therefore can cause infertility. [ 82 ]


Orchitis  is a condition of testicular pain involving swelling, inflammation and possibly infection. Orchitis can be caused by an  autoimmune reaction  (autoimmune orchitis) leading to a reduction in fertility. Autoimmune orchitis is rare in humans, compared to anti-sperm antibodies. [ 1 ]  To study orchitis in the testis, autoimmune orchitis has been induced in the rodent testis. The disease starts with the appearance of testicular antibodies, then movement of  macrophages  and  lymphocytes  from the blood stream into the testis, breaking of the physical interactions between the developing sperm and  Sertoli cells , entry of  neutrophils  or  eosinophils , and finally death of the developing sperm, leading to infertility. [ 83 ] [ 84 ] [ 85 ]


Experiments in rats have examined, in fine detail, the course of testicular events during a bacterial infection. In the short term (3 hours) multiple inflammatory factors are produced and released by testicular  macrophages . Examples are  prostaglandin E2 , [ 86 ] [ 76 ]  inducible  nitric oxide synthase  (iNOS), [ 39 ] [ 87 ]  TNFα [ 88 ]  and IL-1β, although at lower levels than other tissues. [ 86 ] [ 47 ]  Non-immune cells of the testis such as   Sertoli cells  and  Leydig cells  also able to respond to bacteria. [ 63 ] [ 89 ]  During a bacterial infection, testosterone levels and the amount of testicular  interstitial fluid  are reduced. [ 39 ]  Neutrophils enter the testis about 12 hours after infection. [ 39 ]  Importantly, there is damage to the developing sperm, which start to die under severe infections. [ 39 ] [ 90 ]  Despite all the data on the effects of bacteria on normal testis parameters, there is little experimental data regarding its effect on rodent fertility.


Testicular inflammation can be a symptom of the following diseases:  Coxsackie A  virus, [ 91 ] [ 92 ]   varicella  (chicken pox)  [ 91 ] [ 93 ]  human immunodeficiency virus ( HIV ), [ 94 ]   dengue fever , [ 95 ]   Epstein Barr virus -associated infectious mononucleosis, [ 91 ] [ 96 ]   syphilis , [ 97 ]   leprosy , [ 98 ]   tuberculosis . [ 99 ]


Transition nuclear proteins  (TNPs) are  proteins  that are involved in the packaging of  sperm   nuclear   DNA  during  spermiogenesis .  They take the place of  histones  associated with the sperm DNA, and are subsequently themselves replaced by  protamines . [ 1 ]


TNPs in humans include  TNP1  and  TNP2 .


This  protein -related article is a  stub . You can help Wikipedia by  expanding it .


A   varicocele  is, in a man, an abnormal enlargement of the  pampiniform venous plexus  in the  scrotum ; in a woman, it is an abnormal painful swelling to the  embryologically identical  pampiniform venous plexus; it is more commonly called  pelvic compression syndrome . In the male varicocele, this plexus of  veins  drains  blood  from the  testicles  back to the heart. The  vessels  originate in the abdomen and course down through the  inguinal canal  as part of the  spermatic cord  on their way to the  testis . Varicoceles occur in around 15% to 20% of all men. [ 3 ] [ 4 ]  The incidence of varicocele increase with age. [ citation needed ]


Varicocele might be noticed as soft lumps, usually above the testicle and mostly on the left side of the scrotum. [ 5 ]  Right-sided and bilateral varicocele does also occur. Men with varicocele can feel symptoms of pain or heaviness in their scrotum. [ 5 ]  Large varicoceles present as plexus of veins and may be described as a "bag of worms". [ 6 ] [ 7 ]  Varicocele is sometimes discovered when investigating the cause of  male infertility . [ 8 ] [ 9 ]


There are three main theories as to the anatomical cause; the first has to do with the geometry of the veins, wherein the vein on the left side connects to the larger outflowing vein at a right angle, which tends to fail; the second is that testicular valves that are supposed to prevent backflow fail (venous insufficiency) leading to swelling and compression of the valveless  pampiniform plexus ; the third is due to excessive pressure in upstream veins, created by  nutcracker syndrome . [ 10 ]


Often the greatest concern with respect to varicocele is its effect on male fertility. The relationship between varicocele and infertility is unclear. Some men with the condition are fertile, some have sperm that are normal in shape and move normally but are compromised in function, and some have sperm with abnormal shapes or that do not move well. [ 10 ]  Theories as to how varicocele affects sperm function include damage via excess heat caused by the blood pooling and  oxidative stress  on sperm. [ 4 ] [ 10 ] [ 11 ] [ 12 ]


Tobacco smoking  and mutations in the gene expressing  glutathione S-transferase Mu 1  both put men at risk for infertility; these factors may also exacerbate the risk that varicocele will affect fertility. [ 10 ]


Following discovery of the sign of swelling comprising a mass, varicocele can be confirmed with  scrotal ultrasound , which will show dilation of the vessels of the pampiniform plexus to be greater than 2.3 mm. [ 13 ]


A universally accepted system for categorizing varicoceles does not exist, but according to the classification criteria established in 1970 by Dubin and Amelar, most commonly varicoceles are clinically assessed and categorized into three grades as follows: [ 14 ] [ 15 ]


In the Sarteschi (1993) classification system, varicoceles are categorized into five grades: [ 16 ]


Manual examination of scrotum is required for proper interpretation of ultrasound images. During ultrasound examination, diameters of veins in pampiniform plexus are measured and regurgitation is measured. The subject is then instructed to stand up and  Valsalva maneuver  is performed. The diameter is then measured and changes in blood flow direction is recorded to assess any regurgitation. [ 17 ]


The two most common surgical approaches are  retroperitoneal  (abdominal using  laparoscopic surgery ), infrainguinal/subinguinal (below the groin) and  inguinal  (groin using  percutaneous   embolization ). [ 4 ]  Possible complications of this procedure include  hematoma  (bleeding into tissues),  hydrocele  (accumulation of fluid around the affected testicle),  infection , or injury to the scrotal tissue or structures. In addition, injury to the artery that supplies the testicle may occur, resulting in a loss of a testicle. [ 4 ]


Whether having varicocele surgery or embolization improves male fertility is controversial, as good clinical data is lacking. [ 9 ]   There is tentative evidence that varicocelectomy may improve fertility in those with obvious findings and abnormal sperm; [ 4 ]  however, this has a  number needed to treat  of 7 for varicocelectomy and 17 for embolization. [ 18 ] [ 19 ]  There are also studies showing that the regular surgery has no significant effect on infertility. [ 9 ]   A 2012  Cochrane review  (updated in 2021) found tentative but unclear evidence of improved fertility among males treated for varicocele. [ 20 ]  Evidence for  sclerotherapy  is unclear as of 2015. [ 21 ]


Around 15% to 20% of all adult males, up to 35% to 40% of men who are evaluated for male infertility, and around 80% of men who are infertile due to some other cause, have varicocele. [ 3 ] [ 4 ] [ 9 ]


Various vas-occlusive contraceptive methods have been researched for human-use, with interest in both reversible and irreversible methods, with the purpose of finding a suitable alternative to  vasectomy  and possible hormonal contraceptive treatments that are currently being researched. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  Potential methods include  clips ,  plugs ,  valves , polymers, hydrogels, and other devices.


There are numerous vas-occlusive contraceptive methods and devices that have been researched. Outlined here are a few main categories and descriptions.


An intravasal control valve is a reversible valve implanted in the vas deferens with the ability to either inhibit or permit sperm passage depending on the position of the device. Bionyx has developed a T-shaped intravasal control valve composed of gold and stainless steel for use in humans. [ 5 ]  Through rotation, a perforated ball within the T can be used to obstruct sperm flow or allow sperm flow. [ 6 ]  Skilled microsurgery is required for the ICV implant.


Injection of non-toxic and sclerotic chemicals in the vas deferens can result in blockage of sperm transport due to scarring on the vas deferens wall. At least 26 different chemical combinations have been attempted to achieve sterilization. [ 6 ]  A combination of carbolic and n-butyl alpha cyanoacrylate has resulted in complete blockage of the vas deferens through adhesion to the luminal surface. This chemical combination resulted in a 96% azoospermia and a 99% pregnancy prevention eight years follow injection in humans. [ 6 ]  The scar tissue created is not always compact and successful in occluding the vas deferens, which results in the 4% azoospermia failure rate. [ 6 ]  The injection of the chemical combination of ethanol and formaldehyde also resulted in sterility in humans. [ 6 ]  However, these chemical combinations are irreversible.


There are two types of  vas-occlusive plugs : injectable plugs and non-injectable plugs. Injection of medical polyurethane (MPU) to form a plug in the vas deferens resulted in azoospermia in 96% of men, though these result were seen 24 months after injection. [ 6 ] [ 7 ] [ 8 ]  Studies on over 130 men following removal of the plug within five years showed successful restoration of fertility. [ 6 ]  The Shug, short for "silicon plug", is an example of a non-injectable plug, though there is little to no research on the Shug following 2008. [ 8 ]  The Shug is composed of two silicon plugs with accompanying nylon tails that attach to the vas deferens wall. It is surgically inserted into the vas deferens and must also be removed surgically. Shug human trials showed a 97% decrease in sperm motility through the vas deferens. [ 6 ]  However, plugs have been shown to have a lower efficacy rate when compared to traditional vasectomy overall. [ 3 ]


Insertion of an intravasal thread (IVT), also known as an intravasal device (IVD), in the vas deferens has been shown to inhibit sperm transport via mechanical obstruction and the removal of the IVT results in restored vas deferens patency. [ 6 ]  However, this method has differential species-specific results: in pigs, a plastic IVT had no significant effect on sperm count; in dogs, a plastic and polyethylene IVT consistently blocked sperm transport during the experimental period and removal of the device restored sperm transport after a period of two weeks; and in human subjects, a urethane-coated nylon IVT resulted in significantly reduced sperm count but could not guarantee absolute sterility at the same rate as a vasectomy. [ 6 ] [ 3 ]


Reversible inhibition of sperm under guidance ( RISUG ) is a non-toxic polymer gel-based contraceptive that is injected into the lumen of the vas deferens and results in infertility within 10 days following injection. [ 7 ]  RISUG is composed of styrene  maleic anhydride  (SMA) dissolved in  dimethyl sulfoxide  (dimethyl sulfoxide), [ 6 ]  which is believed to both partially occlude the vas deferens by coating the inner walls of the vas deferens with the polymer chemical, while also deactivating the sperm that are able to pass through the partially occluded vas deferens, thereby preventing successful fertilization. [ 7 ]  The exact mechanism of the deactivation effect on sperm is still unknown. [ 3 ] [ 7 ]  RISUG inhibits sperm transport but allows fluid to pass through, which prevents pressure from building up in the vas deferens. [ 7 ]  RISUG has been shown successful in previous human clinical trials in India and is currently undergoing Phase III clinical trials. [ 7 ] [ 9 ] [ 5 ]


Vasalgel was inspired by RISUG and created by the  Parsemus Foundation  in order to be used outside of India. [ 9 ]  Vasalgel is composed of 25% styrene-alt-maleic acid (SMA acid) dissolved in dimethyl sulfoxide. [ 9 ]  The major difference between RISUG and Vasalgel is that Vasalgel is composed of SMA acid without SMA anhydride, which allows for a longer shelf-life, smaller probability of hydrolysis to an acid, and less complex production process. [ 9 ]  Vasalgel was successful in achieving azoospermia in rabbits within 36 days of injection, as well as returned vas deferens patency. [ 9 ]  In 2023, the patent for Vasalgel was acquired by  NEXT Life Sciences , Inc., which plans to bring the technology to market under the name  Plan A for Men . [ 10 ]


Contraline, Inc. is developing a vas-occlusive medical device known as ADAM. ADAM is an injectable hydrogel designed specifically for the dynamic environment of the vas deferens. Unlike RISUG and Vasalgel, which require injection in organic solvent, ADAM is aqueous-based. The ADAM hydrogel is inserted through a minimally-invasive, outpatient procedure. The company has  made advancements in percutaneous (non-surgical) delivery of vas-occlusive devices using ultrasound guidance. Clinical trials on ADAM began in 2022. [ 11 ]


Vas-occlusive contraception methods are expected to have similar side effects to vasectomy, which is generally regarded as a safe and low-risk procedure.


The  Y chromosome  is one of two  sex chromosomes  in  therian mammals  and  other organisms . Along with the  X chromosome , it is part of the  XY sex-determination system , in which the Y is the  sex-determining  chromosome because the presence of the Y chromosome causes  offspring  produced in  sexual reproduction  to be of male  sex . In mammals, the Y chromosome contains the  SRY  gene, which triggers development of  male gonads . The Y chromosome is passed only from male parents to male offspring.


The Y chromosome was identified as a sex-determining chromosome by  Nettie Stevens  at  Bryn Mawr College  in 1905 during a study of the  mealworm   Tenebrio molitor .  Edmund Beecher Wilson  independently discovered the same mechanisms the same year, working with  Hemiptera . Stevens proposed that chromosomes always existed in pairs and that the smaller chromosome (now labelled "Y") was the pair of the X chromosome discovered in 1890 by  Hermann Henking . She realized that the previous idea of  Clarence Erwin McClung , that the X chromosome determines sex, was wrong and that  sex determination  is, in fact, due to the presence or absence of the Y chromosome. In the early 1920s,  Theophilus Painter  determined that X and Y chromosomes determined sex in humans (and other mammals). [ 4 ]


The chromosome was given the name "Y" simply to follow on from Henking's "X" alphabetically. [ 5 ] [ 6 ]  The idea that the Y chromosome was named after its similarity in appearance to the letter "Y" is mistaken. All chromosomes normally appear as an amorphous blob under the microscope and only take on a well-defined shape during  mitosis . This shape is vaguely X-shaped for all chromosomes. It is entirely coincidental that the Y chromosome, during  mitosis , has two very short branches which can look merged under the microscope and appear as the descender of a Y-shape. [ 5 ] : 65–66


Most therian mammals have only one pair of sex chromosomes in each cell. Males have one Y chromosome and one  X chromosome , while females have two X chromosomes. In mammals, the Y chromosome contains a gene,  SRY , which triggers embryonic development as a male. The Y chromosomes of humans and other mammals also contain other genes needed for normal sperm production. [ citation needed ]


There are exceptions, however. Among humans, some males are born two Xs and a Y ("XXY", see  Klinefelter syndrome ), one X and two Ys (see  XYY syndrome ). Some females have three Xs ( Trisomy X ), and some have a single X instead of two Xs ("X0", see  Turner syndrome ). There are other variations in which, during  embryonic development , the  WNT4  gene [ 7 ]  is activated and/or the SRY gene is damaged leading to birth of an  XY female   (Swyer syndrome [ 7 ] ). A Y chromosome may also be present but fail to result in the development of a male phenotype in individuals with  androgen insensitivity syndrome , instead resulting in a female or ambiguous phenotype. In other cases, the SRY gene is copied to the X, leading to birth of an  XX male . [ 8 ]


Many  ectothermic   vertebrates  have no sex chromosomes. [ 9 ]  If these species have different sexes, sex is determined environmentally rather than genetically. For some species, especially  reptiles , sex depends on the incubation temperature. [ 10 ]  Some vertebrates are  hermaphrodites , though hermaphroditic species are most commonly  sequential , meaning the organism switches sex, producing male or female  gametes  at different points in its life, but never producing both at the same time. This is opposed to  simultaneous  hermaphroditism, where the same organism produces male and female gametes at the same time. Most simultaneous hermaphrodite species are invertebrates, and among vertebrates, simultaneous hermaphroditism has only been discovered in a few  orders  of fish. [ 11 ]


The X and Y chromosomes are thought to have evolved from a pair of identical chromosomes, [ 12 ] [ 13 ]  termed  autosomes , when an ancestral animal developed an allelic variation (a so-called "sex locus") and simply possessing this  allele  caused the organism to be male. [ 14 ]  The chromosome with this allele became the Y chromosome, while the other member of the pair became the X chromosome. Over time, genes that were beneficial for males and harmful to (or had no effect on) females either developed on the Y chromosome or were acquired by the Y chromosome through the process of  translocation . [ 15 ]


Until recently, the X and Y chromosomes in mammals were thought to have diverged around 300 million years ago. [ 16 ]  However, research published in 2008 analyzing the  platypus  genome [ 17 ]  suggested that the XY sex-determination system would not have been present more than 166 million years ago, when  monotremes  split from other mammals. [ 18 ]  This re-estimation of the age of the  therian  XY system is based on the finding that sequences that are on the X chromosomes of  marsupials  and  eutherian  mammals are not present on the autosomes of platypus and birds. [ 18 ]  The older estimate was based on erroneous reports that the platypus X chromosomes contained these sequences. [ 19 ] [ 20 ]


Most chromosomes  recombine  during meiosis. However, in males, the X and Y pair in a shared region known as the  pseudoautosomal region  (PAR). [ 21 ]  The PAR undergoes frequent recombination between the X and Y chromosomes, [ 21 ]  but recombination is suppressed in other regions of the Y chromosome. [ 14 ]  These regions contain sex-determining and other male-specific genes. [ 22 ]  Without this suppression, these genes could be lost from the Y chromosome from recombination and cause issues such as infertility. [ 23 ]


The lack of recombination across the majority of the Y chromosome makes it a useful tool in studying  human evolution , since recombination complicates the mathematical models used to trace ancestries. [ 24 ]


By one estimate, the human Y chromosome has lost 1,393 of its 1,438 original genes over the course of its existence, and  linear extrapolation  of this 1,393-gene loss over 300 million years gives a rate of genetic loss of 4.6 genes per million years. [ 25 ]  Continued loss of genes at the rate of 4.6 genes per million years would result in a Y chromosome with no functional genes – that is the Y chromosome would lose complete function – within the next 10 million years, or half that time with the current age estimate of 160 million years. [ 14 ] [ 26 ]   Comparative genomic  analysis reveals that many mammalian species are experiencing a similar loss of function in their heterozygous sex chromosome. Degeneration may simply be the fate of all non-recombining sex chromosomes, due to three common evolutionary forces: high  mutation rate , inefficient  selection , and  genetic drift . [ 14 ]


With a 30% difference between humans and chimpanzees, the Y chromosome is one of the fastest-evolving parts of the  human genome . [ 27 ]  However, these changes have been limited to non-coding sequences and comparisons of the human and  chimpanzee  Y chromosomes (first published in 2005) show that the human Y chromosome has not lost any genes since the divergence of humans and chimpanzees between 6–7 million years ago. [ 28 ]  Additionally, a scientific report in 2012 stated that only one gene had been lost since humans diverged from the  rhesus macaque  25 million years ago. [ 29 ]  These facts provide direct evidence that the  linear extrapolation  model is flawed and suggest that the current human Y chromosome is either no longer shrinking or is shrinking at a much slower rate than the 4.6 genes per million years estimated by the linear extrapolation model. [ citation needed ]


The human Y chromosome is particularly exposed to high mutation rates due to the environment in which it is housed. The Y chromosome is passed exclusively through  sperm , which undergo multiple  cell divisions  during  gametogenesis . Each cellular division provides further opportunity to accumulate base pair mutations. Additionally, sperm are stored in the highly oxidative environment of the  testis , which encourages further mutation. These two conditions combined put the Y chromosome at a greater opportunity of mutation than the rest of the genome. [ 14 ]  The increased mutation opportunity for the Y chromosome is reported by Graves as a factor 4.8. [ 14 ]  However, her original reference obtains this number for the relative mutation rates in male and female germ lines for the lineage leading to humans. [ 30 ]


The observation that the Y chromosome experiences little  meiotic   recombination  and has an accelerated rate of  mutation  and degradative change compared to the rest of the  genome  suggests an evolutionary explanation for the adaptive function of  meiosis  with respect to the main body of genetic information. Brandeis [ 31 ]  proposed that the basic function of meiosis (particularly meiotic recombination) is the conservation of the integrity of the genome, a proposal consistent with the idea that meiosis is an adaptation for  repairing DNA damage . [ 32 ]


Without the ability to recombine during  meiosis , the Y chromosome is unable to expose individual  alleles  to natural selection. Deleterious alleles are allowed to "hitchhike" with beneficial neighbors, thus propagating maladapted alleles into the next generation. Conversely, advantageous alleles may be selected against if they are surrounded by harmful alleles (background selection). Due to this inability to sort through its gene content, the Y chromosome is particularly prone to the accumulation of  "junk" DNA . Massive accumulations of retrotransposable elements are scattered throughout the Y. [ 14 ]  The random insertion of DNA segments often disrupts encoded gene sequences and renders them nonfunctional. However, the Y chromosome has no way of weeding out these "jumping genes". Without the ability to isolate alleles, selection cannot effectively act upon them. [ citation needed ]


A clear, quantitative indication of this inefficiency is the  entropy rate  of the Y chromosome. Whereas all other chromosomes in the  human genome  have entropy rates of 1.5–1.9 bits per nucleotide (compared to the theoretical maximum of exactly 2 for no redundancy), the Y chromosome's entropy rate is only 0.84. [ 33 ]  From the definition of  entropy rate , the Y chromosome has a much lower information content relative to its overall length, and is more redundant.


Even if a well adapted Y chromosome manages to maintain genetic activity by avoiding mutation accumulation, there is no guarantee it will be passed down to the next generation. The population size of the Y chromosome is inherently limited to 1/4 that of autosomes: diploid organisms contain two copies of autosomal chromosomes while only half the population contains 1 Y chromosome. Thus, genetic drift is an exceptionally strong force acting upon the Y chromosome. Through sheer random assortment, an adult male may never pass on his Y chromosome if he only has female offspring. Thus, although a male may have a well adapted Y chromosome free of excessive mutation, it may never make it into the next gene pool. [ 14 ]  The repeat random loss of well-adapted Y chromosomes, coupled with the tendency of the Y chromosome to evolve to have more deleterious mutations rather than less for reasons described above, contributes to the species-wide degeneration of Y chromosomes through  Muller's ratchet . [ 34 ]


As has been already mentioned, the Y chromosome is unable to recombine during  meiosis  like the other human chromosomes; however, in 2003, researchers from  MIT  discovered a process which may slow down the process of degradation.
They found that human Y chromosome is able to "recombine" with itself, using  palindrome   base pair  sequences. [ 35 ]  Such a "recombination" is called  gene conversion .


In the case of the Y chromosomes, the  palindromes  are not  noncoding DNA ; these strings of nucleotides contain functioning genes important for male fertility. Most of the sequence pairs are greater than 99.97% identical. The extensive use of gene conversion may play a role in the ability of the Y chromosome to edit out genetic mistakes and maintain the integrity of the relatively few genes it carries. In other words, since the Y chromosome is single, it has duplicates of its genes on itself instead of having a second, homologous, chromosome. When errors occur, it can use other parts of itself as a template to correct them. [ 35 ]


Findings were confirmed by comparing similar regions of the Y chromosome in humans to the Y chromosomes of  chimpanzees ,  bonobos  and  gorillas . The comparison demonstrated that the same phenomenon of gene conversion appeared to be at work more than 5 million years ago, when humans and the non-human primates diverged from each other. [ 35 ]


Gene conversion  tracts formed during  meiosis  are long, about 2,068 base pairs, and significantly biased towards the fixation of G or C nucleotides (GC biased). [ 36 ]   The  recombination  intermediates preceding gene conversion were found to rarely take the alternate route of crossover recombination. [ 36 ]   The Y-Y gene conversion rate in humans is about 1.52 x 10 -5  conversions/base/year. [ 37 ]  These gene conversion events may reflect a basic function of meiosis, that of conserving the integrity of the genome.


According to some theories, in the terminal stages of the degeneration of the Y chromosome, other chromosomes may increasingly take over genes and functions formerly associated with it and finally, within the framework of this theory, the Y chromosome disappears entirely, and a new sex-determining system arises. [ 14 ] [ neutrality  is  disputed ] [ improper synthesis? ]


Several species of  rodent  in the sister families  Muridae  and  Cricetidae  have reached a stage where the XY system has been modified, [ 38 ] [ 39 ]  in the following ways:


Outside of the rodents, the  black muntjac ,  Muntiacus crinifrons , evolved new X and Y chromosomes through fusions of the ancestral sex chromosomes and  autosomes . [ 45 ]


Modern data cast doubt on the hypothesis that the Y-chromosome will disappear. [ 16 ]  This conclusion was reached by scientists who studied the Y chromosomes of rhesus monkeys. When genomically comparing the Y chromosome of rhesus monkeys and humans, scientists found very few differences, given that humans and rhesus monkeys diverged 30 million years ago. [ 46 ] [ clarification needed ]


Outside of mammals, some organisms have lost the Y chromosome, such as most species of Nematodes. However, in order for the complete elimination of Y to occur, it was necessary to develop an alternative way of determining sex (for example, by determining sex by the ratio of the X chromosome to autosomes), and any genes necessary for male function had to be moved to other chromosomes. [ 16 ]  In the meantime, modern data demonstrate the complex mechanisms of Y chromosome evolution and the fact that the disappearance of the Y chromosome is not guaranteed.


Fisher's principle  outlines why almost all species using  sexual reproduction  have a  sex ratio  of 1:1.  W. D. Hamilton  gave the following basic explanation in his 1967 paper on "Extraordinary sex ratios", [ 47 ]  given the condition that males and females cost equal amounts to produce:


Many groups of organisms in addition to therian mammals have Y chromosomes, but these Y chromosomes do not share common ancestry with therian Y chromosomes. Such groups include monotremes,  Drosophila , some other insects, some fish, some reptiles, and some plants. In  Drosophila melanogaster , the Y chromosome does not trigger male development. Instead, sex is determined by the number of X chromosomes. The  D. melanogaster  Y chromosome does contain genes necessary for male fertility. So XXY  D. melanogaster  are female, and  D. melanogaster  with a single X (X0), are male but sterile. There are some species of Drosophila in which X0 males are both viable and fertile. [ citation needed ]


Other organisms have mirror image sex chromosomes: where the homogeneous sex is the male, with two Z chromosomes, and the female is the heterogeneous sex with a Z chromosome and a W chromosome. [ 48 ]  For example, the ZW sex-determination system is found in  birds ,  snakes , and  butterflies ; the females have ZW sex chromosomes, and males have ZZ sex chromosomes. [ 48 ] [ 49 ] [ 50 ]


There are some species, such as the  Japanese rice fish , in which the XY system is still developing and cross over between the X and Y is still possible. Because the male specific region is very small and contains no essential genes, it is even possible to artificially induce XX males and YY females to no ill effect. [ 51 ]


Monotremes like  platypuses  possess four or five pairs of XY sex chromosomes, each pair consisting of sex chromosomes with homologous regions. The chromosomes of neighboring pairs are partially homologous, such that a chain is formed during  mitosis . [ 19 ]  The first X chromosome in the chain is also partially homologous with the last Y chromosome, indicating that profound rearrangements, some adding new pieces from autosomes, have occurred in history. [ 52 ] [ 53 ] : fig. 5


Platypus sex chromosomes have strong sequence similarity with the avian  Z chromosome , indicating close  homology , [ 17 ]  and the SRY gene so central to sex-determination in most other mammals is apparently not involved in platypus sex-determination. [ 18 ]


The human Y chromosome is composed of about 62 million  base pairs  of  DNA , making it similar in size to  chromosome 19  and represents almost 2% of the total DNA in a male  cell . [ 54 ] [ 55 ]  The human Y chromosome carries 693  genes , 107 of which are  protein-coding . [ 56 ]  However, some genes are repeated, making the number of exclusive  protein-coding  genes just 42. [ 56 ]  The  Consensus Coding Sequence (CCDS) Project  only classifies 63 out of 107 genes, though CCDS estimates are often considered lower bounds due to their conservative classification strategy. [ 57 ]  All single-copy Y-linked genes are  hemizygous  (present on only one chromosome) except in cases of  aneuploidy  such as  XYY syndrome  or  XXYY syndrome . Traits that are inherited via the Y chromosome are called  Y-linked  traits, or holandric traits (from  Ancient Greek  ὅλος  hólos , "whole" + ἀνδρός  andrós , "male"). [ 58 ]


At the end of the  Human Genome Project  (and after many updates) almost half of the Y chromosome remained un-sequenced even in 2021; a different Y chromosome from the HG002 (GM24385) genome was completely sequenced in January 2022 and is included in the new "complete genome" human  reference genome  sequence, CHM13. [ 56 ]  The complete  sequencing  of a human Y chromosome was shown to contain 62,460,029 base pairs and 41 additional  genes . [ 56 ]  This added 30 million base pairs, [ 56 ]  but it was discovered that the Y chromosome can vary a lot in size between individuals, from 45.2 million to 84.9 million base pairs. [ 59 ]


Since almost half of the human Y sequence was unknown before 2022, it could not be screened out as contamination in microbial sequencing projects. As a result, the NCBI RefSeq bacterial genome database mistakenly includes some Y chromosome data. [ 56 ]


The human Y chromosome is normally unable to recombine with the X chromosome, except for small pieces of  pseudoautosomal regions  (PARs) at the  telomeres  (which comprise about 5% of the chromosome's length). These regions are relics of ancient  homology  between the X and Y chromosomes. The bulk of the Y chromosome, which does not recombine, is called the "NRY", or non-recombining region of the Y chromosome. [ 68 ]   Single-nucleotide polymorphisms  (SNPs) in this region are used to trace direct paternal ancestral lines.


More specifically, PAR1 is at 0.1–2.7 Mb. PAR2 is at 56.9–57.2 Mb. The non-recombining region (NRY) or male-specific region (MSY) sits between. Their sizes is now known perfectly from CHM13: 2.77 Mb and 329.5 kb. Until CHM13 the data in PAR1 and PAR2 was just copied over from X chromosome. [ 59 ]


The following are some of the gene count estimates of human Y chromosome. Because researchers use different approaches to  genome annotation  their predictions of the  number of genes  on each chromosome varies (for technical details, see  gene prediction ). Among various projects, CCDS takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes. [ 69 ]


In general, the human Y chromosome is extremely gene poor—it is one of the largest  gene deserts  in the human genome. Disregarding  pseudoautosomal  genes, genes encoded on the human Y chromosome include:


Diseases linked to the Y chromosome typically involve an  aneuploidy , an atypical number of chromosomes.


Males can lose the Y chromosome in a subset of cells, known as  mosaic  loss. Mosaic loss is strongly associated with age, [ 79 ]  and smoking is another important risk factor for mosaic loss. [ 80 ]


Mosaic loss may be related to health outcomes, indicating that the Y chromosome plays important roles outside of sex determination. [ 80 ] [ 81 ]  Males with a higher percentage of  hematopoietic   stem cells  lacking the Y chromosome have a higher risk of certain  cancers  and have a shorter life expectancy. [ 81 ]  In many cases, a cause and effect relationship between the Y chromosome and health outcomes has not been determined, and some propose loss of the Y chromosome could be a "neutral  karyotype  related to normal  aging ". [ 82 ]  However, a 2022 study showed that mosaic loss of the Y chromosome causally contributes to  fibrosis ,  heart risks , and mortality. [ 83 ]


Further studies are needed to understand how mosaic Y chromosome loss may contribute to other sex differences in health outcomes, such as how male smokers have between 1.5 and 2 times the risk of non-respiratory cancers as female smokers. [ 84 ] [ 85 ]  Potential countermeasures identified so far include not smoking or  stopping smoking  and at least one potential drug that "may help counteract the harmful effects of the chromosome loss" is under investigation. [ 86 ] [ 87 ] [ better source needed ]


Y chromosome microdeletion  (YCM) is a family of genetic disorders caused by missing genes in the Y chromosome. Many affected men exhibit no symptoms and lead normal lives. However, YCM is also known to be present in a significant number of men with reduced fertility or reduced sperm count. [ citation needed ]


This results in the person presenting a female  phenotype  (i.e., is born with female-like genitalia) even though that person possesses an XY  karyotype . The lack of the second X results in infertility. In other words, viewed from the opposite direction, the person goes through  defeminization  but fails to complete  masculinization . [ citation needed ]


The cause can be seen as an incomplete Y chromosome: the usual karyotype in these cases is 45X, plus a fragment of Y. This usually results in defective testicular development, such that the infant may or may not have fully formed male genitalia internally or externally. The full range of ambiguity of structure may occur, especially if  mosaicism  is present. When the Y fragment is minimal and nonfunctional, the child is usually a girl with the features of  Turner syndrome  or  mixed gonadal dysgenesis .


Klinefelter syndrome (47, XXY) is not an  aneuploidy  of the Y chromosome, but a condition of having an extra X chromosome, which usually results in defective postnatal testicular function. The mechanism is not fully understood; it does not seem to be due to direct interference by the extra X with expression of Y genes. [ citation needed ]


47, XYY syndrome (simply known as XYY syndrome) is caused by the presence of a single extra copy of the Y chromosome in each of a male's cells. 47, XYY males have one X chromosome and two Y chromosomes, for a total of 47 chromosomes per cell. Researchers have found that an extra copy of the Y chromosome is associated with increased stature and an increased incidence of learning problems in some boys and men, but the effects are variable, often minimal, and the vast majority do not know their karyotype. [ 88 ]


In 1965 and 1966  Patricia Jacobs  and colleagues published a chromosome survey of 315 male patients at
 Scotland 's only special security hospital for the  developmentally disabled ,
finding a higher than expected number of patients to have an extra Y chromosome. [ 89 ]  The authors of this study wondered "whether an extra Y chromosome predisposes its carriers to unusually aggressive behaviour", and this conjecture "framed the next fifteen years of research on the human Y chromosome". [ 90 ]


Through studies over the next decade, this conjecture was shown to be incorrect: the elevated crime rate of XYY males is due to lower median intelligence and not increased aggression, [ 91 ]  and increased height was the only characteristic that could be reliably associated with XYY males. [ 92 ]  The "criminal karyotype" concept is therefore inaccurate. [ 88 ]


There are also  XXXY syndrome  and  XXXXY syndrome .


The following Y-chromosome-linked diseases are rare, but notable because of their elucidation of the nature of the Y chromosome.


Greater degrees of Y chromosome polysomy (having more than one extra copy of the Y chromosome in every cell, e.g., XYYY) are considerably more rare. The extra genetic material in these cases can lead to skeletal abnormalities, dental abnormalities, decreased IQ, delayed development, and respiratory issues, but the severity features of these conditions are variable. [ 93 ]


XX male syndrome  occurs due to a  genetic recombination  in the formation of the male  gametes , causing the  SRY  portion of the Y chromosome to move to the X chromosome. [ 8 ]  When such an X chromosome is present in a zygote, male gonads develop because of the SRY gene. [ 8 ]


In human  genetic genealogy  (the application of  genetics  to  traditional genealogy ), use of the information contained in the Y chromosome is of particular interest because, unlike other chromosomes, the Y chromosome is passed exclusively from father to son, on the patrilineal line.  Mitochondrial DNA , maternally inherited to both sons and daughters, is used in an analogous way to trace the matrilineal line. [ citation needed ]


Research is currently investigating whether male-pattern neural development is a direct consequence of Y-chromosome-related gene expression or an indirect result of Y-chromosome-related  androgenic hormone  production. [ 94 ]


In 1974, male chromosomes were discovered in fetal cells in the blood circulation of women. [ 95 ]


In 1996, it was found that male fetal progenitor cells could persist postpartum in the maternal blood stream for as long as 27 years. [ 96 ]


A 2004 study at the  Fred Hutchinson Cancer Research Center , Seattle, investigated the origin of male chromosomes found in the peripheral blood of women who had not had male progeny. A total of 120 subjects (women who had never had sons) were investigated, and it was found that 21% of them had male DNA in their peripheral blood. The subjects were categorised into four groups based on their case histories: [ 97 ]


The study noted that 10% of the women had never been pregnant before, raising the question of where the Y chromosomes in their blood could have come from. The study suggests that possible reasons for occurrence of male chromosome microchimerism could be one of the following: [ 97 ]


A 2012 study at the same institute has detected cells with the Y chromosome in multiple areas of the brains of deceased women. [ 98 ]


Y chromosome microdeletion   (YCM)  is a family of  genetic disorders  caused by missing genes in the  Y chromosome . Many men with YCM exhibit no symptoms and lead normal lives. It is present in a significant number of men with reduced  fertility . [ 1 ]  Reduced sperm production varies from  oligozoospermia , significant lack of sperm, or  azoospermia , complete lack of sperm.


The mechanism of  mutation  is not different for Y-chromosome microdeletion. However, the ability to repair it differs from other chromosomes. The human Y chromosome is passed directly from father to son, and is not protected against accumulating copying errors, whereas other chromosomes are error corrected by recombining genetic information from mother and father. This may leave  natural selection  as the primary repair mechanism for the Y chromosome. [ citation needed ]


Y chromosome microdeletion is currently diagnosed by extracting DNA from  leukocytes  in a man's blood sample, mixing it with some of the about 300 known  genetic markers  for  sequence-tagged sites  (STS) on the Y chromosome, and then using  polymerase chain reaction  amplification and  gel electrophoresis  in order to test whether the DNA sequence corresponding to the selected markers is present in the DNA. [ citation needed ]


Such procedures can test only the integrity of a tiny part of the overall 23 million  base pair  long Y chromosome. Therefore, the sensitivity of such tests depends on the choice and number of markers used. Present diagnostic techniques can only discover certain types of deletions and mutations on a chromosome and give therefore no complete picture of genetic causes of infertility. They can only demonstrate the presence of some defects, but not the absence of any possible genetic defect on the chromosome. [ citation needed ]


The preferred test for genetic mutation, namely complete  DNA sequencing  of a patient's Y chromosome, is too expensive for use in  epidemiological research  or clinical diagnostics. [ citation needed ]


In up to 20% of men with reduced  sperm count , some form of YCM has been detected. [ 2 ]


Microdeletions in the Y chromosome have been found at a much higher rate in  infertile  men than in fertile controls [ 3 ]  and the correlation found may still go up as improved  genetic testing  techniques for the Y chromosome are developed. [ citation needed ]


Much study has been focused upon the " azoospermia factor locus " (AZF), at Yq11. [ 4 ]  A specific partial deletion of AZFc called  gr/gr deletion  is significantly associated with  male infertility  among Caucasians in Europe and the Western Pacific region. [ 5 ]


Additional genes associated with  spermatogenesis  in men and reduced fertility upon Y chromosome deletions include  RBM ,  DAZ ,  SPGY , and  TSPY . [ 6 ]


Childbirth , also known as  labour ,  parturition  and  delivery , is the completion of  pregnancy  where one or more  babies  exits the internal environment of the  mother  via  vaginal delivery  or  caesarean section . [ 7 ]  In 2019, there were about 140.11 million human  births  globally. [ 9 ]  In  developed countries , most deliveries occur in  hospitals , [ 10 ] [ 11 ]  while in  developing countries  most are  home births . [ 12 ]


The most common childbirth method worldwide is vaginal delivery. [ 6 ]  It involves four  stages of labour : the  shortening  and  opening of the cervix  during the first stage, descent and birth of the baby during the second, the delivery of the  placenta  during the third, and the recovery of the mother and infant during the fourth stage, which is referred to as the  postpartum . The first stage is characterised by abdominal cramping or also back pain in the case of back labour, [ 13 ]  that typically lasts half a minute and occurs every 10 to 30 minutes. [ 14 ]  Contractions gradually become stronger and closer together. [ 15 ]  Since the pain of childbirth correlates with contractions, the pain becomes more frequent and strong as the labour progresses. The second stage ends when the infant is fully expelled. The third stage is the delivery of the  placenta . [ 16 ]  The fourth stage of labour involves the recovery of the mother,  delayed clamping of the umbilical cord , and monitoring of the  neonate . [ 17 ]  As of 2014, [update]  all major health organisations advise that immediately following a  live birth , regardless of the delivery method, that the infant be placed on the mother's chest (termed  skin-to-skin contact ), and to delay neonate procedures for at least one to two hours or until the baby has had its first  breastfeeding . [ 18 ] [ 19 ] [ 20 ]


Vaginal delivery is generally recommended as a first option. Cesarean section can lead to increased risk of complications and a significantly slower recovery. There are also many natural benefits of a vaginal delivery in both mother and baby. Various methods may help with pain, such as  relaxation techniques ,  opioids , and  spinal blocks . [ 15 ]  It is best practice to limit the amount of interventions that occur during labour and delivery such as an elective cesarean section, however in some cases a scheduled cesarean section must be planned for a successful delivery and recovery of the mother. An emergency cesarean section may be recommended if unexpected complications occur or little to no progression through the birthing canal is observed in a vaginal delivery.
Each year, complications from pregnancy and childbirth result in about 500,000  birthing deaths , seven million women have serious long-term problems, and 50 million women giving birth have negative health outcomes following delivery, most of which occur in the  developing world . [ 5 ]  Complications in the mother include  obstructed labour ,  postpartum bleeding ,  eclampsia , and  postpartum infection . [ 5 ]  Complications in the baby include  lack of oxygen at birth  (birth asphyxia),  birth trauma , and  prematurity . [ 4 ] [ 21 ]


The most prominent sign of labour is strong repetitive  uterine contractions . Pain in contractions has been described as feeling similar to very strong  menstrual cramps . Crowning may be experienced as an intense stretching and burning. The  Lamaze  method of childbirth teaches that making noises such as moaning, groaning, grunting, repeating words over and over, and any sound that one's body may wish to naturally make may help to relieve pain and help labour to progress.  According to Lamaze, "While the media would have you believe that all birthing women scream, in reality, it's not the most common noise." They say that screaming may be a sign that the labouring woman is beginning to panic and the support team should help her back to regulated breathing. [ 22 ]


Back labour  is a complication that occurs during childbirth when a fetus exhibits posterior presentation (i.e. when the fetus is facing the mother's navel), instead of the typical anterior presentation. [ 23 ]  This leads to more intense contractions, and causes pain in the lower back that persists between contractions as the fetus’ occiput exerts pressure on the mother's sacrum. [ 24 ]


Another prominent sign of labour is the  rupture of membranes , commonly known as "water breaking".  During pregnancy, a baby is surrounded and cushioned by a fluid-filled sac. Usually the sac ruptures at the beginning of or during labour.   It may cause a gush of fluid or leak in an intermittent or constant flow of small amounts from a woman's vagina.  The fluid is clear or pale yellow.   If the amniotic sac has not yet broken during labour the health care provider may break it in a technique called an  amniotomy .  In an amniotomy a thin plastic hook is used to make a small opening in the sac, causing the water to break. [ 25 ]  If the sac breaks before labour starts, it's called a  prelabour rupture of membranes .   Contractions will typically start within 24 hours after the water breaks. If not, the care provider will generally begin  labour induction  within 24 to 48 hours.  If the baby is preterm (less than 37 weeks of pregnancy), the healthcare provider may use a medication to delay delivery. [ 26 ]


There is currently no definitive scientific explanation for why labour is painful. According to studies, during pregnancy, the  myometrium  (the muscle part of the uterus) is greatly denervated. [ 27 ]  Stretch receptors in the uterus disappear during pregnancy, and stretch receptors in the cervix disappear at the onset of labour. [ 28 ]  Consequently, the reason for labour pain has only been theorised, not ascertained. One theory is that the pain results from the buildup of chemicals released during physical exertion. The second leading theory is that the pain results from the vasoconstriction of uterine blood vessels in the myometrium; each contraction squeezes the blood vessels, reducing blood flow and causing some  hypoxia .


During the later stages of gestation, there is an increase in abundance of  oxytocin , a hormone that is known to evoke feelings of contentment, reductions in anxiety, and feelings of calmness and security around the mate. [ 29 ]  Oxytocin is further released during labour when the fetus stimulates the cervix and vagina, and it is believed that it plays a major role in the bonding of a mother to her infant and in the establishment of maternal behaviour. Studies show that the father of the child also has an increase in oxytocin levels following contact with the infant and parents with higher oxytocin levels showed more responsiveness and synchrony in their interactions with their infant.  The act of  nursing  a child also causes a release of oxytocin to help the baby get milk more easily from the nipple. [ 30 ] [ 31 ]


Station  refers to the relationship of the fetal presenting part to the level of the  ischial spines . When the presenting part is at the ischial spines the station is 0 (synonymous with engagement). If the presenting fetal part is above the spines, the distance is measured and described as minus stations, which range from −1 to −4  cm . If the presenting part is below the ischial spines, the distance is stated as plus stations ( +1 to +4 cm). At +3 and +4 the presenting part is at the perineum and can be seen. [ 32 ]


The fetal head may temporarily change shape (becoming more elongated or cone shaped) as it moves through the birth canal. This change in the shape of the fetal head is called  molding  and is much more prominent in women having their first vaginal delivery. [ 33 ]


Cervical ripening  is the physical and chemical changes in the cervix to prepare it for the stretching that will take place as the fetus moves out of the uterus and into the birth canal. A scoring system called a  Bishop score  can be used to judge the degree of cervical ripening to predict the timing of labour and delivery of the infant or for women at risk for preterm labour.  It is also used to judge when a woman will respond to  induction of labour  for a postdate pregnancy or other medical reasons.  There are several methods of inducing cervical ripening which will allow the uterine contractions to effectively dilate the cervix. [ 34 ]


Vaginal delivery involves four stages of labour: the  shortening  and  opening of the cervix  during the first stage, descent and birth of the baby during the second, the delivery of the  placenta  during the third, and the 4th stage of recovery which lasts until two hours after the delivery. The first stage is characterised by abdominal cramping or back pain that typically lasts around half a minute and occurs every 10 to 30 minutes. [ 14 ]  The contractions (and pain) gradually becomes stronger and closer together. [ 15 ]  The second stage ends when the infant is fully expelled. In the third stage, the delivery of the placenta. [ 16 ]  The fourth stage of labour involves recovery, the uterus beginning to contract to pre-pregnancy state,  delayed clamping of the umbilical cord , and monitoring of the neonatal tone and vitals. [ 17 ]  As of 2014, [update]  all major health organisations advise that immediately following a  live birth , regardless of the delivery method, that the infant be placed on the mother's chest, termed  skin-to-skin contact , and delaying routine procedures for at least one to two hours or until the baby has had its first breastfeeding. [ 18 ] [ 19 ] [ 20 ]


Definitions of the onset of labour include:


Many women are known to experience what has been termed the "nesting instinct". Women report a spurt of energy shortly before going into labour. [ 38 ]  Common signs that labour is about to begin may include what is known as  lightening , which is the process of the baby moving down from the rib cage with the head of the baby engaging deep in the pelvis. The pregnant woman may then find breathing easier, since her lungs have more room for expansion, but pressure on her bladder may cause more frequent need to void (urinate).  Lightening may occur a few weeks or a few hours before labour begins, or even not until labour has begun. [ 38 ]  Some women also experience an increase in vaginal discharge several days before labour begins when the "mucus plug", a thick plug of  mucus  that blocks the opening to the uterus, is pushed out into the vagina.  The mucus plug may become dislodged days before labour begins or not until the start of labour. [ 38 ]


While inside the uterus the baby is enclosed in a fluid-filled membrane called the  amniotic sac .  Shortly before, at the beginning of, or during labour the  sac ruptures . Once the sac ruptures, termed "the water breaks", the baby is at risk for infection and the mother's medical team will assess the need to  induce labour  if it has not started within the time they believe to be safe for the infant. [ 38 ]


The first stage of labour is divided into latent and active phases, where the latent phase is sometimes included in the definition of labour, [ 39 ]  and sometimes not. [ 40 ]


The  latent phase  is generally defined as beginning at the point at which the woman perceives regular  uterine contractions . [ 41 ]  In contrast,  Braxton Hicks contractions , which are contractions that may start around 26 weeks gestation and are sometimes called "false labour", are infrequent, irregular, and involve only mild cramping. [ 42 ]  Braxton Hicks contractions are the uterine muscles preparing to deliver the infant.


Cervical effacement , which is the thinning and stretching of the  cervix , and  cervical dilation  occur during the closing weeks of  pregnancy .  Effacement is usually complete or near-complete and dilation is about 5 cm by the end of the latent phase. [ 43 ]  The degree of cervical effacement and dilation may be felt during a vaginal examination.


The  active phase  of labour has geographically differing definitions.  The World Health Organization describes the active first stage as "a period of time characterised by regular painful uterine contractions, a substantial degree of cervical effacement and more rapid cervical dilatation from 5 cm until full dilatation for first and subsequent labours”. [ 44 ]  In the US, the definition of active labour was changed from 3 to 4 cm, to 5 cm of  cervical dilation  for multiparous women, mothers who had given birth previously, and at 6 cm for nulliparous women, those who had not given birth before. [ 45 ]  This was done in an effort to increase the rates of vaginal delivery. [ 46 ]


Health care providers may assess the mother's progress in labour by performing a cervical exam to evaluate the cervical dilation, effacement, and station. These factors form the  Bishop score . The Bishop score can also be used as a means to predict the success of an  induction of labour .


During effacement, the cervix becomes incorporated into the lower segment of the uterus. During a contraction, uterine muscles contract causing shortening of the upper segment and drawing upwards of the lower segment, in a gradual expulsive motion. [ 47 ]  The presenting fetal part then is permitted to descend. Full dilation is reached when the cervix has widened enough to allow passage of the baby's head, around 10 cm dilation for a term baby.


A standard duration of the latent first stage has not been established and can vary widely from one woman to another. However, the duration of active first stage (from 5 cm until full cervical dilatation) usually does not extend beyond 12 hours in the first labour("primiparae"), and usually does not extend beyond 10 hours in subsequent labours ("multiparae"). [ 48 ]


Dystocia of labour , also called "dysfunctional labour" or "failure to progress", is difficult labour or abnormally slow progress of labour, involving progressive cervical dilatation or lack of descent of the fetus.  Friedman's Curve, developed in 1955, was for many years used to determine labour dystocia. However, more recent medical research suggests that the Friedman curve may not be currently [ when? ]  applicable. [ 49 ] [ 50 ]