When the follicle matures and reaches 8–10 mm in diameter it starts to secrete significant amounts of  estradiol .  Normally in humans only one follicle becomes dominant and survives to grow to 18–30 mm in size and ovulate, the remaining follicles in the cohort undergo  atresia .  The sharp increase in estradiol production by the dominant follicle (possibly along with a decrease in  gonadotrophin  surge-attenuating factor) cause a positive effect on the hypothalamus and pituitary and rapid  GnRH  pulses occur and an  LH  surge results.


The increase in serum  estradiol  levels causes a decrease in FSH production by inhibiting  GnRH  production in the hypothalamus. [ 15 ]


The decrease in serum FSH level causes the smaller follicles in the current cohort to undergo atresia as they lack sufficient sensitivity to FSH to survive.  Occasionally two follicles reach the 10 mm stage at the same time by chance and as both are equally sensitive to FSH both survive and grow in the low FSH environment and thus two ovulations can occur in one cycle possibly leading to non-identical ( dizygotic ) twins. [ citation needed ]


FSH stimulates primary  spermatocytes  to undergo the first division of  meiosis , to form secondary spermatocytes.


FSH enhances the production of  androgen-binding protein  by the  Sertoli cells  of the  testes  by binding to  FSH receptors  on their  basolateral  membranes, [ 16 ]  and is critical for the initiation of  spermatogenesis .


Follicle-stimulating hormone is typically measured in the early  follicular phase  of the menstrual cycle, typically day three to five, counted from last menstruation. At this time, the levels of estradiol (E2) and progesterone are at the lowest point of the  menstrual cycle . FSH levels in this time is often called  basal FSH  levels, to distinguish from the increased levels when approaching ovulation. [ 17 ]


FSH is measured in  international units  (IU). For Human Urinary FSH, one IU is defined as the amount of FSH that has an activity corresponding to 0.11388 mg of pure Human Urinary FSH. [ 18 ]  For recombinant FSH, one IU corresponds to approximately 0.065 to 0.075  μg  of a "fill-by-mass" product. [ 19 ]
The mean values for women before  ovulation  are around (3.8-8.8) IU/L. After ovulation these levels drop to between (1.8-5.1) IU/L. At the mid of the  menstrual cycle  it reaches its highest value, between (4.5-22.5) IU/L. During  menopause , the values goes up even more, between (16.74-113.59) IU/L.
For men, the mean values are around (16.74-113.59) IU/L.


FSH levels are normally low during  childhood  and, in females, high after  menopause .


The most common reason for high serum FSH concentration is in a female who is undergoing or has recently undergone  menopause . High levels of FSH indicate that the normal restricting feedback from the gonad is absent, leading to an unrestricted pituitary FSH production. FSH may contribute to postmenopausal osteoporosis and cardiovascular disease. [ 20 ]


If high FSH levels occur during the reproductive years, it is abnormal. Conditions with high FSH levels include:


Most of these conditions are associated with subfertility or infertility. Therefore, high FSH levels are an indication of subfertility or infertility.


Diminished secretion of FSH can result in failure of gonadal function (hypogonadism). This condition is typically manifested in males as failure in production of normal numbers of sperm. In females, cessation of reproductive cycles is commonly observed. [ citation needed ]
Conditions with very low FSH secretions are:


Isolated FSH deficiency due to mutations in the gene for β-subunit of FSH is rare with 13 cases reported in the literature up to 2019. [ 23 ]


FSH is used commonly in infertility therapy, mainly for  ovarian hyperstimulation  as part of  IVF . In some cases, it is used in  ovulation induction  for reversal of  anovulation  as well.


FSH is available mixed with LH activity in various  menotropins  including more purified forms of urinary  gonadotropins  such as  Menopur , as well as without LH activity as recombinant FSH (Gonapure, Gonal F, Follistim, Follitropin alpha).


Elevated FSH receptor levels have been detected in the endothelia of tumor vasculature in a very wide range of solid tumors.  FSH binding is thought to upregulate neovascularization via at least two mechanisms – one in the  VEGF  pathway, and the other VEGF independent – related to the development of umbilical vasculature when physiological. This presents possible use of FSH and FSH-receptor antagonists as an anti-tumor angiogenesis therapy (cf.  avastin  for current anti-VEGF approaches). [ 24 ]


Growth hormone  ( GH ) or  somatotropin , also known as  human growth hormone  ( hGH  or  HGH ) in its human form, is a  peptide hormone  that stimulates growth,  cell  reproduction, and cell regeneration in humans and other animals. It is thus important in  human development . GH also stimulates production of  insulin-like growth factor 1  (IGF-1) and increases the concentration of  glucose  and  free fatty acids . [ 1 ] [ 2 ]  It is a type of  mitogen  which is specific only to the  receptors  on certain types of cells. GH is a 191- amino acid , single-chain  polypeptide  that is synthesized, stored and secreted by  somatotropic cells  within the lateral wings of the  anterior pituitary  gland.


A  recombinant  form of HGH called  somatropin  ( INN ) is used as a  prescription drug  to treat children's growth disorders and adult  growth hormone deficiency . In the United States, it is only available legally from pharmacies by prescription from a licensed health care provider. In recent years in the United States, some health care providers are prescribing growth hormone in the elderly to increase  vitality . While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. Many of the functions of HGH remain unknown. [ 3 ]


In its role as an  anabolic  agent, HGH has been used by competitors in sports since at least 1982  and has been banned by the  IOC  and  NCAA . Traditional  urine  analysis does not detect  doping  with HGH, so the ban was not enforced until the early 2000s, when  blood tests  that could distinguish between natural and artificial HGH were starting to be developed. Blood tests conducted by  WADA  at the  2004 Olympic Games  in  Athens, Greece , targeted primarily HGH. [ 3 ]  Use of the drug for performance enhancement is not currently approved by the  FDA .


GH has been studied for use in raising livestock more efficiently in  industrial agriculture  and several efforts have been made to obtain governmental approval to use GH in livestock production. These uses have been controversial. In the United States, the only FDA-approved use of GH for livestock is the use of a cow-specific form of GH called  bovine somatotropin  for increasing milk production in dairy cows. Retailers are permitted to label containers of milk as produced with or without bovine somatotropin.


The names  somatotropin  ( STH ) or  somatotropic hormone  refer to the  growth hormone  produced naturally in animals and extracted from carcasses. Hormone extracted from human cadavers is abbreviated  hGH . The main growth hormone produced by  recombinant DNA  technology has the approved generic name ( INN )  somatropin  and the brand name  Humatrope [ 4 ]  and is properly abbreviated rhGH in the scientific literature. Since its introduction in 1992, Humatrope has been a banned sports doping agent [ 5 ]  and in this context is referred to as HGH.


The term  growth hormone  has been incorrectly applied to refer to  anabolic   sex hormones  in the European  beef hormone controversy , which initially restricts the use of  estradiol ,  progesterone ,  testosterone ,  zeranol ,   melengestrol acetate  and  trenbolone acetate . [ 6 ]


Genes for human growth hormone, known as   growth hormone 1  (somatotropin; pituitary growth hormone) and  growth hormone 2  (placental growth hormone; growth hormone variant), are localized in the q22-24 region of chromosome 17 [ 7 ] [ 8 ]  and are closely related to  human chorionic somatomammotropin  (also known as  placental lactogen ) genes. GH, human chorionic somatomammotropin, and  prolactin  belong to  a group of homologous hormones  with growth-promoting and lactogenic activity.


The major isoform of the human growth hormone is a protein of 191  amino acids  and a molecular weight of 22,124  daltons . The structure includes four helices necessary for functional interaction with the GH receptor. It appears that, in structure, GH is evolutionarily homologous to prolactin and chorionic somatomammotropin. Despite marked structural similarities between growth hormone from different  species , only human and  Old World monkey  growth hormones have significant effects on the human  growth hormone receptor . [ 9 ]


Several  molecular  isoforms of GH exist in the pituitary gland and are released to blood. In particular, a variant of approximately 20 kDa originated by an alternative splicing is present in a rather constant 1:9 ratio, [ 10 ]  while recently an additional variant of ~ 23-24 kDa has also been reported in post-exercise states at higher proportions. [ 11 ]  This variant has not been identified, but it has been suggested to coincide with a 22 kDa glycosylated variant of 23 kDa identified in the pituitary gland. [ 12 ]  Furthermore, these variants circulate partially bound to a protein ( growth hormone-binding protein , GHBP), which is the truncated part of the  growth hormone receptor , and an acid-labile subunit (ALS).  [ citation needed ]


Secretion of growth hormone (GH) in the pituitary is regulated by the  neurosecretory  nuclei of the  hypothalamus .
These cells release the peptides  growth hormone-releasing hormone  (GHRH or  somatocrinin ) and  growth hormone-inhibiting hormone  (GHIH or  somatostatin ) into the  hypophyseal portal  venous blood surrounding the pituitary.
GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion. [ 13 ]


Somatotropic cells  in the  anterior pituitary  gland then synthesize and secrete GH in a pulsatile manner, in response to these stimuli by the hypothalamus.
The largest and most predictable of these GH peaks occurs about an hour after onset of sleep with plasma levels of 13 to 72 ng/mL. [ 14 ]
Maximal secretion of GH may occur within minutes of the onset of   slow-wave  (SW) sleep (stage III or IV). [ 15 ]   Otherwise there is wide variation between days and individuals. Nearly fifty percent of GH secretion occurs during the third and fourth  NREM sleep  stages. [ 16 ]
Surges of secretion during the day occur at 3- to 5-hour intervals. [ 3 ]  The plasma concentration of GH during these peaks may range from 5 to even 45 ng/mL. [ 17 ]
Between the peaks, basal GH levels are low, usually less than 5 ng/mL for most of the day and night. [ 14 ]  Additional analysis of the pulsatile profile of GH described in all cases less than 1 ng/ml for basal levels while maximum peaks were situated around 10-20 ng/mL. [ 18 ] [ 19 ]


A number of factors are known to affect GH secretion, such as age, sex, diet, exercise, stress, and other hormones. [ 3 ]  Young adolescents secrete GH at the rate of about 700 μg/day, while healthy adults secrete GH at the rate of about 400 μg/day. [ 20 ]  Sleep deprivation generally suppresses GH release, particularly after early adulthood. [ 21 ]


Stimulators [ quantify ]  of growth hormone (GH) secretion include:


Inhibitors [ quantify ]  of GH secretion include:


In addition to control by endogenous and stimulus processes, a number of foreign compounds ( xenobiotics  such as drugs and  endocrine disruptors ) are known to influence GH secretion and function. [ 38 ]


Effects of growth hormone on the tissues of the body can generally be described as  anabolic  (building up).  Like most other peptide hormones, GH acts by interacting with a specific  receptor  on the surface of cells. [ citation needed ]


Increased height during childhood is the most widely known effect of GH.  Height appears to be stimulated by at least two mechanisms:


In addition to increasing height in children and adolescents, growth hormone has many other effects on the body:


GH has a short  biological half-life  of about 10 to 20 minutes. [ 45 ] [ 46 ]


The most common disease of GH excess is a pituitary tumor composed of somatotroph cells of the anterior pituitary. These somatotroph  adenomas  are benign and grow slowly, gradually producing more and more GH. For years, the principal clinical problems are those of GH excess. Eventually, the adenoma may become large enough to cause headaches, impair vision by pressure on the optic nerves, or cause deficiency of other pituitary hormones by displacement. [ citation needed ]


Prolonged GH excess thickens the bones of the jaw, fingers and toes, resulting in heaviness of the jaw and increased size of digits, referred to as  acromegaly . Accompanying problems can include sweating, pressure on nerves (e.g.,  carpal tunnel syndrome ), muscle weakness, excess  sex hormone-binding globulin  (SHBG), insulin resistance or even a rare form of  type 2 diabetes , and reduced sexual function. [ citation needed ]


GH-secreting tumors are typically recognized in the fifth decade of life. It is extremely rare for such a tumor to occur in childhood, but, when it does, the excessive GH can cause excessive growth, traditionally referred to as  pituitary gigantism . [ citation needed ]


Surgical removal is the usual treatment for GH-producing tumors. In some circumstances, focused radiation or a GH antagonist such as  pegvisomant  may be employed to shrink the tumor or block function. Other drugs like  octreotide  (somatostatin agonist) and  bromocriptine  ( dopamine agonist ) can be used to block GH secretion because both somatostatin and  dopamine  negatively inhibit GHRH-mediated GH release from the anterior pituitary. [ 47 ]


The effects of  growth hormone (GH) deficiency  vary depending on the age at which they occur.  Alterations in  somatomedin  can result in growth hormone deficiency with two known mechanisms; failure of tissues to respond to  somatomedin , or failure of the  liver  to produce somatomedin. [ 48 ]   Major manifestations of GH deficiency in children are  growth failure , the development of a  short stature , and delayed sexual maturity.  In adults, somatomedin alteration contributes to increased  osteoclast  activity, resulting in weaker bones that are more prone to  pathologic fracture  and  osteoporosis . [ 48 ]  However, deficiency is rare in adults, with the most common cause being a  pituitary adenoma . [ 49 ]   Other adult causes include a continuation of a childhood problem, other structural lesions or  trauma , and very rarely idiopathic GHD. [ 49 ]


Adults with GHD "tend to have a relative increase in fat mass and a relative decrease in muscle mass and, in many instances, decreased energy and quality of life". [ 49 ]


Diagnosis of GH deficiency involves a multiple-step diagnostic process, usually culminating in GH stimulation tests to see if the patient's pituitary gland will release a pulse of GH when provoked by various stimuli. [ citation needed ]


Several studies, primarily involving patients with  GH deficiency , have suggested a crucial role of GH in both mental and emotional well-being and maintaining a high energy level. Adults with GH deficiency often have higher rates of  depression  than those without. [ 50 ]   While  GH replacement therapy  has been proposed to treat depression as a result of GH deficiency, the long-term effects of such therapy are unknown. [ 50 ]


GH has also been studied in the context of  cognitive function , including learning and memory. [ 51 ]  GH in humans appears to improve cognitive function and may be useful in the treatment of patients with cognitive impairment that is a result of GH deficiency. [ 51 ]


GH is used as replacement therapy in adults with GH deficiency of either childhood-onset or adult-onset (usually as a result of an acquired pituitary tumor). In these patients, benefits have variably included reduced fat mass, increased lean mass, increased bone density, improved lipid profile, reduced cardiovascular risk factors, and improved psychosocial well-being. Long acting growth hormone (LAGH) analogues are now available for treating growth hormone deficiency both in children and adults. These are once weekly injections as compared to conventional growth hormone which has to be taken as daily injections. LAGH injection 4 times a month has been found to be as safe and effective as daily growth hormone injections. [ 52 ]


GH can be used to treat conditions that produce short stature but are not related to deficiencies in GH. However, results are not as dramatic when compared to short stature that is solely attributable to deficiency of GH.  Examples of other causes of shortness often treated with GH are  Turner syndrome , Growth failure secondary to  chronic kidney disease  in children, [ 53 ]   Prader–Willi syndrome ,  intrauterine growth restriction , and severe  idiopathic short stature . Higher ("pharmacologic") doses are required to produce significant acceleration of growth in these conditions, producing blood levels well above normal ("physiologic"). [ citation needed ]


One version of rHGH has also been FDA approved for maintaining muscle mass in  wasting  due to  AIDS . [ 54 ]


Off-label  prescription of HGH is controversial and may be illegal. [ 55 ]


Claims for GH as an anti-aging treatment date back to 1990 when the  New England Journal of Medicine  published a study wherein GH was used to treat 12 men over 60. [ 56 ]   At the conclusion of the study, all the men showed statistically significant increases in lean body mass and bone mineral density, while the control group did not.  The authors of the study noted that these improvements were the opposite of the changes that would normally occur over a 10- to 20-year aging period.  Despite the fact the authors at no time claimed that GH had reversed the aging process itself, their results were misinterpreted as indicating that GH is an effective anti-aging agent. [ 57 ] [ 58 ] [ 59 ]  This has led to organizations such as the controversial  American Academy of Anti-Aging Medicine  promoting the use of this hormone as an "anti-aging agent". [ 60 ]


A Stanford University School of Medicine  meta-analysis  of clinical studies on the subject published in early 2007 showed that the application of GH on healthy elderly patients increased muscle by about 2 kg and decreased body fat by the same amount. [ 57 ]  However, these were the only positive effects from taking GH.  No other critical factors were affected, such as bone density, cholesterol levels, lipid measurements, maximal oxygen consumption, or any other factor that would indicate increased fitness. [ 57 ]  Researchers also did not discover any gain in muscle strength, which led them to believe that GH merely let the body store more water in the muscles rather than increase muscle growth. This would explain the increase in lean body mass. [ citation needed ]


GH has also been used experimentally to treat  multiple sclerosis , to enhance  weight loss  in  obesity , as well as in  fibromyalgia ,  heart failure ,  Crohn's disease  and  ulcerative colitis , and burns. GH has also been used experimentally in patients with  short bowel syndrome  to lessen the requirement for intravenous  total parenteral nutrition . [ citation needed ]


In 1990, the US Congress passed an omnibus crime bill, the  Crime Control Act of 1990 , that amended the  Federal Food, Drug, and Cosmetic Act , that classified  anabolic steroids  as  controlled substances  and added a new section that stated that a person who "knowingly distributes, or possesses with intent to distribute, human growth hormone for any use in humans other than the treatment of a disease or other recognized medical condition, where such use has been authorized by the Secretary of Health and Human Services" has committed a  felony . [ 61 ] [ 62 ]


The  Drug Enforcement Administration  of the US Department of Justice considers off-label prescribing of HGH to be illegal, and to be a key path for illicit distribution of HGH. [ 55 ]   This section has also been interpreted by some doctors, most notably [ 63 ]  the authors of a commentary article published in the  Journal of the American Medical Association  in 2005, as meaning that  prescribing  HGH off-label may be considered illegal. [ 64 ]   And some articles in the popular press, such as those criticizing the pharmaceutical industry for marketing drugs for off-label use (with concern of ethics violations) have made strong statements about whether doctors can prescribe HGH off-label: "Unlike other prescription drugs, HGH may be prescribed only for specific uses. U.S. sales are limited by law to treat a rare growth defect in children and a handful of uncommon conditions like short bowel syndrome or Prader-Willi syndrome, a congenital disease that causes reduced muscle tone and a lack of hormones in sex glands." [ 65 ] [ 66 ]   At the same time, anti-aging clinics where doctors prescribe, administer, and sell HGH to people are big business. [ 65 ] [ 67 ]   In a 2012 article in  Vanity Fair , when asked how HGH prescriptions far exceed the number of adult patients estimated to have HGH-deficiency, Dragos Roman, who leads a team at the FDA that reviews drugs in endocrinology, said "The F.D.A. doesn't regulate off-label uses of H.G.H. Sometimes it's used appropriately. Sometimes it's not." [ 67 ]


Injection site reactions  are common.  More rarely, patients can experience  joint swelling, joint pain,  carpal tunnel syndrome , and an increased risk of  diabetes . [ 57 ]    In some cases, the patient can produce an immune response against GH.  GH may also  be a risk factor for  Hodgkin's lymphoma . [ 68 ]


One survey of adults that had been treated with replacement cadaver GH (which has not been used anywhere in the world since 1985) during childhood showed a mildly increased incidence of colon cancer and prostate cancer, but linkage with the GH treatment was not established. [ 69 ]


The first description of the use of GH as a doping agent was Dan Duchaine's "Underground Steroid handbook" which emerged from California in 1982; it is not known where and when GH was first used this way. [ 70 ]


Athletes in many sports have used human growth hormone in order to attempt to enhance their athletic performance. Some recent studies have not been able to support claims that human growth hormone can improve the athletic performance of professional male athletes. [ 71 ] [ 72 ] [ 73 ]   Many athletic societies ban the use of GH and will issue sanctions against athletes who are caught using it. However, because GH is a potent endogenous protein, it is very difficult to detect GH doping. In the United States, GH is legally available only by prescription from a medical doctor. [ citation needed ]


To capitalize on the idea that GH might be useful to combat aging, companies selling  dietary supplements  have websites selling products linked to GH in the advertising text, with medical-sounding names described as "HGH Releasers". Typical ingredients include amino acids, minerals, vitamins, and/or herbal extracts, the combination of which are described as causing the body to make more GH with corresponding beneficial effects. In the United States, because these products are marketed as dietary supplements, it is illegal for them to contain GH, which is a drug. Also, under United States law, products sold as dietary supplements cannot have claims that the supplement treats or prevents any disease or condition, and the advertising material must contain a statement that the health claims are not approved by the FDA. The FTC and the FDA do enforce the law when they become aware of violations. [ 74 ]


In the United States, it is legal to give a bovine GH to dairy cows to increase milk production, and is legal to use GH in raising cows for beef; see article on  Bovine somatotropin ,  cattle feeding ,  dairy farming  and the  beef hormone controversy . [ citation needed ]


The use of GH in  poultry farming  is illegal in the United States. [ 75 ] [ 76 ]  Similarly, no chicken meat for sale in Australia is administered hormones. [ 77 ]


Several companies have attempted to have a version of GH for use in pigs (porcine somatotropin) approved by the FDA but all applications have been withdrawn. [ 78 ]


Genentech  pioneered the use of  recombinant  human growth hormone for human therapy, which was approved by the FDA in 1985. [ citation needed ]


Prior to its production by recombinant DNA technology, growth hormone used to treat deficiencies was extracted from the  pituitary glands  of  cadavers .  Attempts to create a wholly synthetic HGH failed.  Limited supplies of HGH resulted in the restriction of HGH therapy to the treatment of idiopathic short stature. [ 79 ]   Very limited clinical studies of growth hormone derived from an Old World monkey, the  rhesus macaque , were conducted by John C. Beck and colleagues in Montreal, in the late 1950s. [ 80 ]  The study published in 1957, which was conducted on "a 13-year-old male with well-documented hypopituitarism secondary to a crainiophyaryngioma," found that: "Human and monkey growth hormone resulted in a significant enhancement of nitrogen storage ... (and) there was a retention of potassium, phosphorus, calcium, and sodium. ... There was a gain in body weight during both periods. ... There was a significant increase in urinary excretion of aldosterone during both periods of administration of growth hormone. This was most marked with the human growth hormone. ... Impairment of the glucose tolerance curve was evident after 10 days of administration of the human growth hormone. No change in glucose tolerance was demonstrable on the fifth day of administration of monkey growth hormone." [ 80 ]   The other study, published in 1958, was conducted on six people: the same subject as the Science paper; an 18-year-old male with statural and sexual retardation and a skeletal age of between 13 and 14 years; a 15-year-old female with well-documented hypopituitarism secondary to a craniopharyngioma; a 53-year-old female with carcinoma of the breast and widespread skeletal metastases;  a 68-year-old female with advanced postmenopausal osteoporosis; and a healthy 24-year-old medical student without any clinical or laboratory evidence of systemic disease. [ 81 ]


In 1985, unusual cases of  Creutzfeldt–Jakob disease  were found in individuals that had received cadaver-derived HGH ten to fifteen years previously.  Based on the assumption that infectious prions causing the disease were transferred along with the cadaver-derived HGH, cadaver-derived HGH was removed from the market. [ 20 ]


In 1985, biosynthetic human growth hormone replaced pituitary-derived human growth hormone for therapeutic use in the U.S. and elsewhere. [ citation needed ]


As of 2005, recombinant growth hormones available in the United States (and their manufacturers) included Nutropin ( Genentech ), Humatrope ( Lilly ), Genotropin ( Pfizer ), Norditropin ( Novo ),  and Saizen ( Merck Serono ). In 2006, the U.S. Food and Drug Administration (FDA) approved a version of  rHGH  called  Omnitrope  (Sandoz). [ 82 ]   A sustained-release form of growth hormone, Nutropin Depot (Genentech and Alkermes) was approved by the FDA in 1999, allowing for fewer injections (every 2 or 4 weeks instead of daily); however, the product was discontinued by Genentech/Alkermes in 2004 for financial reasons (Nutropin Depot required significantly more resources to produce than the rest of the Nutropin line [ 83 ] ).


Luteinizing hormone  ( LH , also known as  luteinising hormone , [ 1 ]   lutropin  and sometimes  lutrophin [ 2 ] ) is a  hormone  produced by  gonadotropic cells  in the  anterior pituitary gland . The production of LH is regulated by  gonadotropin-releasing hormone  (GnRH) from the hypothalamus. [ 3 ]  In females, an acute rise of LH known as an  LH surge , triggers  ovulation [ 4 ]  and development of the  corpus luteum . In males, where LH had also been called  interstitial cell–stimulating hormone  ( ICSH ), [ 5 ]  it stimulates  Leydig cell  production of  testosterone . [ 4 ]  It acts synergistically with follicle-stimulating hormone ( FSH ).


The term luteinizing comes from the  Latin  "luteus", meaning "yellow". This is in reference to the  corpus luteum , which is a mass of cells that forms in an ovary after an ovum (egg) has been discharged. The corpus luteum is so named because it often has a distinctive yellow color. The process of forming the corpus luteum is known as " luteinization ", and thus the hormone that triggers this process is termed the "luteinizing" hormone.


LH is a  heterodimeric   glycoprotein . Each  monomeric  unit is a  glycoprotein  molecule; one alpha and one beta subunit make the full, functional protein.


Its structure is similar to that of the other  glycoprotein hormones ,  follicle-stimulating hormone  (FSH),  thyroid-stimulating hormone  (TSH), and  human chorionic gonadotropin  (hCG). The protein dimer contains 2 glycopeptidic subunits (labeled alpha- and beta- subunits) that are non-covalently associated: [ 6 ]


The different composition of these  oligosaccharides  affects bioactivity and speed of degradation. The biologic  half-life  of LH is 20 minutes, shorter than that of  FSH (3–4 hours) and hCG (24 hours). [ citation needed ]  The biological  half-life  of LH is 23 hours subcutaneous [ 7 ]  or terminal half life of 10-12 hours. [ 8 ]


The  gene  for the  alpha subunit  is located on  chromosome 6q 12.21.


The luteinizing hormone  beta subunit  gene is localized in the LHB/CGB gene cluster on  chromosome 19q 13.32. In contrast to the alpha gene activity, beta LH subunit gene activity is restricted to the pituitary gonadotropic cells. It is regulated by the  gonadotropin-releasing hormone  from the   hypothalamus . GnRH activates Egr1 which interacts with transcription factors NR5A1 and PITX1 at the gene promoter to up-regulate LHB transcription. [ 9 ] [ 10 ]


In both males and females, LH works upon endocrine cells in the gonads to produce androgens.


LH supports  theca cells  in the ovaries that provide  androgens  and hormonal precursors for  estradiol  production. At the time of  menstruation , FSH initiates  follicular  growth, specifically affecting  granulosa cells . [ 11 ]  With the rise in  estrogens , LH receptors are also expressed on the maturing follicle, which causes it to produce more  estradiol . Eventually, when the follicle has fully matured, a spike in  17α-hydroxyprogesterone  production by the follicle inhibits the production of  estrogens . Previously, the preovulatory LH surge was attributed to a decrease in estrogen-mediated  negative feedback  of  GnRH  in the  hypothalamus , subsequently stimulating the release of LH from the  anterior pituitary . [ 12 ]  Some studies, however, attribute the LH surge to positive feedback from  estradiol  after production by the dominant follicle exceeds a certain threshold. Exceptionally high levels of estradiol induce hypothalamic production of  progesterone , which stimulates elevated GnRH secretion, triggering a surge in LH. [ 13 ]  The increase in LH production only lasts for 24 to 48 hours. This "LH surge" triggers  ovulation , thereby not only releasing the egg from the follicle, but also initiating the conversion of the residual follicle into a  corpus luteum  that, in turn, produces progesterone to prepare the  endometrium  for a possible  implantation . LH is necessary to maintain luteal function for the second two weeks of the menstrual cycle. If  pregnancy  occurs, LH levels will decrease, and luteal function will instead be maintained by the action of hCG ( human chorionic gonadotropin ), a hormone very similar to LH but secreted from the new placenta.


Gonadal steroids ( estrogens  and androgens) generally have negative feedback effects on GnRH-1 release at the level of the hypothalamus and at the gonadotropes, reducing their sensitivity to GnRH. Positive feedback by estrogens also occurs in the gonadal axis of female mammals and is responsible for the midcycle surge of LH that stimulates ovulation. Although estrogens inhibit  kisspeptin  (Kp) release from kiss1 neurons in the ARC, estrogens stimulate Kp release from the Kp neurons in the AVPV. As estrogens' levels gradually increase the positive effect predominates, leading to the LH surge.  GABA -secreting neurons that innervate GnRH-1 neurons also can stimulate GnRH-1 release. These GABA neurons also possess ERs and may be responsible for the GnRH-1 surge. Part of the inhibitory action of endorphins on GnRH-1 release is through inhibition of these GABA neurons. Rupture of the ovarian follicle at ovulation causes a drastic reduction in estrogen synthesis and a marked increase in secretion of progesterone by the corpus luteum in the ovary, reinstating a predominantly negative feedback on hypothalamic secretion of GnRH-1. [ 14 ]


LH acts upon the  Leydig cells  of the  testis  and is regulated by   gonadotropin-releasing hormone  (GnRH). [ 15 ]  The Leydig cells produce  testosterone  under the control of LH. LH binds to LH receptors on the membrane surface of Leydig cells. Binding to this receptor causes an increase in cyclic adenosine monophosphate (cAMP), a secondary messenger, which allows cholesterol to translocate into the mitochondria. Within the mitochondria, cholesterol is converted to pregnenolone by CYP11A1. [ 16 ]  Pregnenolone is then converted to dehydroepiandrosterone (DHEA). [ 17 ]  DHEA is then converted to androstenedione by 3β-hydroxysteroid dehydrogenase (3β-HSD) [ 18 ]  and then finally converted to testosterone by  17β-hydroxysteroid dehydrogenase  (HSD17B). The onset of puberty is controlled by two major hormones: FSH initiates spermatogenesis and LH signals the release of testosterone, [ 19 ]  an  androgen  that exerts both endocrine activity and intratesticular activity on  spermatogenesis .


LH is released from the pituitary gland, and is controlled by pulses of   gonadotropin-releasing hormone . When bloodstream testosterone levels are low, the pituitary gland is stimulated to release LH. [ 15 ]  As the levels of testosterone increase, it will act on the pituitary through a negative feedback loop and inhibit the release of GnRH and LH consequently. [ 20 ]  Androgens (including testosterone and  dihydrotestosterone ) inhibit monoamine oxidase (MAO) in the pineal gland, leading to increased melatonin and reduced LH and FSH by melatonin-induced increase of Gonadotropin-Inhibitory Hormone (GnIH) [ 21 ]  synthesis and secretion. Testosterone can also be aromatized into  estradiol  (E2) to inhibit LH. E2 decreases pulse amplitude and responsiveness to GnRH from the hypothalamus onto the pituitary. [ 22 ]


Changes in LH and testosterone blood levels and pulse secretions are induced by changes in  sexual arousal  in human males. [ 23 ]


Luteinizing hormone receptors are located in areas of the brain associated with  cognitive function . [ 24 ]  The role of LH role in the  central nervous system  (CNS) may be of relevance to understanding and treating post-menopausal cognitive decline. [ 25 ]


Some research has observed an inverse relationship between circulating LH and CNS LH levels. [ 26 ]  After ovariectomy (a procedure used to mimic menopause) in female mice, circulating LH levels surge while CNS levels of LH fall. [ 24 ]  Treatments that lower circulating LH restore LH levels in the CNS. [ 24 ]


LH levels are normally low during  childhood  and in women, high after  menopause . Since LH is secreted as pulses, it is necessary to follow its concentration over a sufficient period of time to get proper information about its blood level.


During reproductive years, typical levels are between 1 and 20 IU/L. Physiologic high LH levels are seen during the LH surge (v.s.) and typically last 48 hours.


In males over 18 years of age, reference ranges have been estimated to be 1.8–8.6 IU/L. [ 28 ]


LH is measured in  international units  (IU). When quantifying the amount of LH in a sample in IUs, it is important to know which international standard your lot of LH was calibrated against since they can vary broadly from year to year.  For human urinary LH, one IU is defined as 1/189th of an ampule denoted 96/602 and distributed by the  NIBSC , corresponding to approximately 0.04656 μg of LH protein for a single IU, but older standard versions are still widely in use. [ 29 ] [ 30 ]


The detection of a surge in release of luteinizing hormone indicates impending  ovulation . LH can be detected by  urinary  ovulation predictor kits (OPK, also LH-kit) that are performed, typically daily, around the time ovulation may be expected. [ 32 ]   A conversion from a negative to a positive reading would suggest that ovulation is about to occur within 24–48 hours, giving women two days to engage in  sexual intercourse  or  artificial insemination  with the intention of  conceiving . [ 33 ]


The recommended testing frequency differs between manufacturers. For example, the Clearblue test is taken daily, and an increased frequency does not decrease the risk of missing an LH surge. [ 34 ]  On the other hand, the Chinese company  Nantong Egens Biotechnology  recommends using their test twice per day. [ 35 ]  If testing once per day, no significant difference has been found between testing LH in the morning versus in the evening, in relation to conception rates, [ 36 ]  and recommendations of what time in the day to take the test varies between manufacturers and healthcare workers. [ 37 ]  Tests may be read manually using a color-change paper strip, or digitally with the assistance of reading electronics.


Tests for luteinizing hormone may be combined with testing for  estradiol  in tests such as the Clearblue  fertility monitor . [ medical citation needed ]


The sensitivity of LH tests are measured in  milli international unit , with tests commonly available in the range 10–40 m.i.u. (the lower the number, the higher the sensitivity). [ citation needed ]


As sperm can stay viable in the woman for several days, LH tests are not recommended for  contraceptive  practices, as the LH surge typically occurs after the beginning of the fertile window. [ citation needed ]


In children with  precocious puberty  of pituitary or central origin, LH and FSH levels may be in the reproductive range instead of the low levels typical for their age.


During the reproductive years, relatively elevated LH is frequently seen in patients with  polycystic ovary syndrome ; however, it would be unusual for them to have LH levels outside of the normal reproductive range.


Persistently high LH levels are indicative of situations where the normal restricting feedback from the gonad is absent, leading to a pituitary production of  both LH and FSH. While this is typical in menopause, it is abnormal in the reproductive years. There it may be a sign of:


Note: A medical drug for inhibiting luteinizing hormone secretion is  butinazocine . [ 38 ]


Diminished secretion of LH can result in failure of gonadal function (hypogonadism). This condition is typically manifest in males as failure in production of normal numbers of sperm. In females,  amenorrhea   is commonly observed. Conditions with very low LH secretions include:


Luteinizing hormone is available mixed with FSH in the form of  menotropin , and other forms of urinary  gonadotropins . More purified forms of urinary gonadotropins may reduce the LH portion in relation to FSH. Recombinant luteinizing hormone is available as lutropin alfa (Luveris). [ 41 ]


Phosphorylation  is a biochemical process that involves the addition of phosphate to an organic compound.  Steroidogenesis  entails processes by which cholesterol is converted to biologically active steroid hormones. A study shows that LH via a PKA signaling pathway regulates the phosphorylation and localization of DRP1 within mitochondria of the  steroidogenic  cells of the ovary. [ 42 ]


The  melanocortins  are a family of  neuropeptide hormones  which are the ligands of the  melanocortin receptors . [ 1 ]  The melanocortin system consists of melanocortin receptors, ligands, and accessory proteins. The genes of the melanocortin system are found in  chordates . [ 2 ]  Melanocortins were originally named so because their earliest known function was in  melanogenesis . It is now known that the melanocortin system regulates diverse functions throughout the body, including  inflammatory response ,  fibrosis , melanogenesis,  steroidogenesis , energy homeostasis, sexual function, and  exocrine gland  function. [ 3 ] [ 4 ] [ 1 ]


There are four endogenous melanocortin  agonists  which are derived from post-transcriptional processing of the precursor molecule  proopiomelanocortin  (POMC). [ 5 ]  They are  adrenocorticotropic hormone  (ACTH),  α-melanocyte stimulating hormone  (MSH),  β-MSH , and  γ-MSH . In addition to agonists which activate melanocortin receptors, there are two antagonists which inhibit receptor activity, agouti and  agouti-related protein  (AgRP). Lastly, the ligand  β-defensin  3 acts as a neutral melanocortin receptor antagonist. [ 6 ]


The five melanocortin receptors are seven-transmembrane  G-protein coupled receptors  with differing ligand affinities, tissue and cell type expression, and downstream functions. [ 7 ]  MC1R is expressed on  melanocytes ,  macrophages , epithelial cells, endothelial cells,  fibroblasts ,  monocytes  and numerous other immune cells, but is also present in brain, testis, and intestine. [ 8 ]  Its main functions are in melanogenesis and anti-inflammatory signaling. [ 9 ]  MC2R is expressed in the adrenal cortex and adipocytes and promotes steroidogenesis. [ 10 ]  MC3R and MC4R are primarily expressed in the brain and regulate energy homeostasis. [ 1 ]  MC3R is additionally involved in immunomodulation while MC4R has a role in sexual function. [ 11 ] [ 12 ]  MC5R is highly expressed in skin and adrenal glands and has a role in exocrine function. [ 13 ]  MC2R is activated exclusively by ACTH, whereas the other 4 receptors can be activated by ACTH, α-MSH, β-MSH, and γ-MSH, although the binding affinities differ. For all the melanocortin receptors, binding of an agonistic ligand activates the receptor, leading to dissociation of the G protein and activation of the enzyme adenyl cyclase. Adenyl cyclase then cleaves ATP to generate the second messenger cyclic AMP (cAMP), which in turn activates multiple downstream pathways.


There are two known accessory proteins belonging to the melanocortin system which modulate function of the receptors. These are melanocortin-2-receptor accessory protein (MRAP) and MRAP2. [ 14 ]


FDA-approved


In 2019 the FDA approved the first drug targeting melanocortin receptors,  Vyleesi  ( Bremelanotide ) which was developed by Palatin Technologies, Inc.  The Melanocortin system has been largely unexplored in drug development but recent approvals, its novelty and wide-spread application across indications has led it to the frontier of new discoveries in medicine. Since Vyleesi approval  multiple companies have initiated drug discovery programs targeting the melanocortin system. Bremelanotide (Vyleesi) is approved for treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. [ 15 ]  At therapeutic dose levels, it activates MC1R and MC4R. [ 16 ]


Setmelanotide  (Imcivree) is an MC4R agonist approved for chronic weight management in patients with genetic obesity. [ 17 ] [ 18 ]


Afamelanotide  (Scenesse) is an MC1R agonist approved for patients with erythropoietic protoporphyria to increase pain-free light exposure. [ 19 ]


Clinical trials


PL9643, an ophthalmic solution, is being tested in phase 3 clinical trials to determine safety and efficacy in patients with dry eye. [ 20 ]  PL9643 activates MC1R, MC3R, MC4R and MC5R. Completed Phase 2 studies demonstrated positive results for the treatment of dry eye disease. [ 21 ]


Dersimelagon (MT-7117) is an orally administered MC1R agonist being tested in phase 3 clinical trials to evaluate safety and tolerability in patients with erythropoietic protoporphyria or X-linked protoporphyria. [ 22 ]


Resomelagon (AP1189) is an orally administered MC1R and MC3R agonist being tested in three phase 2 clinical trials to study safety and efficacy in patients with rheumatoid arthritis and idiopathic membranous nephropathy. [ 23 ] [ 24 ] [ 25 ]


The melanocortin system is one of the mammalian body's tools to regulate food intake in a push-pull fashion. [ 26 ]  The only neurons known to release melanocortins are located in the arcuate nucleus of the hypothalamus. However,  melanocortins are also produced by keratinocytes  in response to UV exposure.  Accordingly, there is a subpopulation called POMC neurons and one called AgRP neurons. [ 27 ]  When POMC neurons release α-MSH, appetite is decreased. On the other hand, when AgRP neurons release AgRP, appetite is stimulated.


Leptin , the energy surfeit hormone, and  Ghrelin , the hunger hormone, are upstream regulators of the melanocortin system in the brain. [ 27 ]  These hormones also regulate the release of peptides other than the melanocortins. Disturbance of the leptin-melanocortin pathway can lead to early onset obesity as well as various metabolic disorders and suppressed immune function.  [ 28 ]


This  biochemistry  article is a  stub . You can help Wikipedia by  expanding it .


The  melanocyte-stimulating hormones , known collectively as  MSH , also known as  melanotropins  or  intermedins , are a family of  peptide hormones  and  neuropeptides  consisting of  α-melanocyte-stimulating hormone  (α-MSH),  β-melanocyte-stimulating hormone  (β-MSH), and  γ-melanocyte-stimulating hormone  (γ-MSH) that are produced by cells in the  pars intermedia  of the  anterior lobe of the pituitary gland .


Synthetic   analogues  of α-MSH, such as  afamelanotide  (melanotan I; Scenesse),  melanotan II , and  bremelanotide  (PT-141), have been developed and researched.


The various forms of MSH are generated from different cleavages of the  proopiomelanocortin  protein, which also yields other important  neuropeptides  like  adrenocorticotropic hormone . [ 1 ] : 554    [ 2 ]


Melanocytes  in skin make and secrete MSH in response to  ultraviolet  light, where it increases synthesis of  melanin . [ 3 ] : 441    Some neurons in  arcuate nucleus  of the  hypothalamus  make and secrete α-MSH in response to  leptin ; [ 3 ] : 626  [ 4 ] : 419     α-MSH is also made and secreted in the  anterior lobe of the pituitary gland . [ 5 ] : 1210


Acting through  melanocortin 1 receptor , α-MSH stimulates the production and release of  melanin  (a process referred to as  melanogenesis ) by  melanocytes  in  skin  and  hair . [ 5 ] : 1210


Acting in the hypothalamus, α-MSH suppresses appetite. [ 4 ] : 419    α-MSH secreted in the hypothalamus also contributes to  sexual arousal . [ 6 ]


In some animals (such as the claw-toed frog  Xenopus laevis ) production of MSH is increased when the animal is in a dark location. This causes pigment to be dispersed in pigment cells in the toad's skin, making it become darker, and harder for  predators  to spot. The pigment cells are called  melanophores  and therefore, in amphibians, the hormone is often called melanophore-stimulating hormone.


An increase in MSH will cause darker skin in humans too. Pigmentation increases in humans during  pregnancy ; though the exact endocrine cause is not known, α- and β-melanocyte-stimulating hormone are thought to be involved. [ 7 ]   Cushing's disease  due to excess  adrenocorticotropic hormone  (ACTH) may also result in hyperpigmentation, such as  acanthosis nigricans  in the  axilla . Most people with primary  Addison's disease  have darkening ( hyperpigmentation ) of the skin, including areas not exposed to the sun; characteristic sites are skin creases (e.g. of the hands), nipple, and the inside of the cheek (buccal mucosa), new scars become hyperpigmented, whereas older ones do not darken. This occurs because MSH and ACTH share the same precursor molecule,  proopiomelanocortin  (POMC).


Different levels of MSH are not the major cause of variation in  skin colour . However, in many  red-headed  people, and other people who do not  tan  well, there are variations in their hormone  receptors , causing them to not respond to MSH in the blood.


The different forms of MSH belong to a group called the  melanocortins . This group includes ACTH, α-MSH, β-MSH, and γ-MSH; these peptides are all cleavage products of a large precursor peptide called  proopiomelanocortin  (POMC). α-MSH is the most important melanocortin for pigmentation.


The different forms of MSH have the following  amino acid   sequences :


Synthetic  analogues  of α-MSH have been developed for human use. Two of the better known are  afamelanotide  (melanotan I) in testing by  Clinuvel Pharmaceuticals  and  bremelanotide  by  Palatin Technologies . Others include  modimelanotide  and  setmelanotide .


1RW5 ,  2Q98 ,  3D48 ,  3EW3 ,  3MZG ,  3N06 ,  3N0P ,  3NCB ,  3NCC ,  3NCE ,  3NCF ,  3NPZ


NM_000948 NM_001163558


NM_001163530 NM_011164


NP_000939 NP_001157030


NP_001157002 NP_035294


Prolactin  ( PRL ), also known as  lactotropin  and  mammotropin , is a  protein  best known for its role in enabling mammals to  produce milk . It is influential in over 300 separate processes in various vertebrates, including humans. [ 5 ]  Prolactin is secreted from the  pituitary gland  in response to eating, mating, estrogen treatment, ovulation and nursing.  It is secreted heavily in pulses in between these events. Prolactin plays an essential role in metabolism, regulation of the  immune system  and pancreatic development. [ 6 ] [ 7 ]


Discovered in non-human animals around 1930 by  Oscar Riddle [ 8 ]  and confirmed in humans in 1970 by  Henry Friesen , [ 9 ]  prolactin is a  peptide hormone ,  encoded by the  PRL   gene . [ 10 ]


In mammals, prolactin is associated with milk production; in fish it is thought to be related to the control of water and salt balance. Prolactin also acts in a  cytokine -like manner and as an important regulator of the immune system. It has important cell cycle-related functions as a growth-, differentiating- and anti- apoptotic  factor. As a growth factor, binding to cytokine-like receptors, it influences  hematopoiesis  and  angiogenesis  and is involved in the regulation of blood clotting through several pathways. The hormone acts in  endocrine ,  autocrine , and  paracrine  manners through the  prolactin receptor  and numerous  cytokine receptors . [ 5 ]


Pituitary prolactin secretion is regulated by endocrine neurons in the  hypothalamus . The most important of these are the neurosecretory  tuberoinfundibulum  (TIDA) neurons of the  arcuate nucleus  that secrete  dopamine  (a.k.a. Prolactin Inhibitory Hormone) to act on the  D 2  receptors  of  lactotrophs , causing  inhibition  of prolactin secretion.  Thyrotropin-releasing hormone  has a  stimulatory  effect on prolactin release, although prolactin is the only  anterior pituitary  hormone whose principal control is inhibitory.


Several variants and forms are known per species. Many fish have variants  prolactin A  and  prolactin B . Most vertebrates, including humans, also have the closely related somatolactin. In humans, 14, 16, and 22 kDa variants exist. [ 11 ]


Prolactin has a wide variety of effects. It stimulates the  mammary glands  to produce milk ( lactation ): increased serum concentrations of prolactin during  pregnancy  cause enlargement of the mammary glands and prepare for milk production, which normally starts when levels of  progesterone  fall by the end of pregnancy and a suckling stimulus is present. Prolactin plays an important role in  maternal behavior . [ 12 ]


It has been shown in rats and sheep that prolactin affects lipid synthesis differentially in mammary and adipose cells. Prolactin deficiency induced by bromocriptine increased lipogenesis and insulin responsiveness in adipocytes while decreasing them in the mammary gland. [ 13 ]


In general,  dopamine  inhibits prolactin [ 14 ]  but this process has feedback mechanisms. [ 15 ]


Elevated levels of prolactin decrease the levels of sex hormones— estrogen  in women and  testosterone  in men. [ 16 ]  The effects of mildly elevated levels of prolactin are much more variable, in women, substantially increasing or decreasing estrogen levels.


Prolactin is sometimes classified as a  gonadotropin [ 17 ]  although in humans it has only a weak luteotropic effect while the effect of suppressing classical gonadotropic hormones is more important. [ 18 ]  Prolactin within the normal reference ranges can act as a weak gonadotropin, but at the same time suppresses  gonadotropin-releasing hormone  secretion. The exact mechanism by which it inhibits gonadotropin-releasing hormone is poorly understood. Although expression of prolactin receptors have been demonstrated in rat hypothalamus, the same has not been observed in gonadotropin-releasing hormone neurons. [ 19 ]   Physiologic levels of prolactin in males enhance  luteinizing hormone -receptors in  Leydig cells , resulting in testosterone secretion, which leads to  spermatogenesis . [ 20 ]


Prolactin also stimulates proliferation of  oligodendrocyte precursor cells . These cells differentiate into  oligodendrocytes , the cells responsible for the formation of  myelin  coatings on  axons  in the  central nervous system . [ 21 ]


Other actions include contributing to  pulmonary surfactant  synthesis of the fetal  lungs  at the end of the pregnancy and  immune tolerance  of the fetus by the maternal organism during pregnancy. Prolactin promotes  neurogenesis  in maternal and  fetal  brains. [ 22 ] [ 23 ]


In  music psychology , it is conjectured that prolactin may play a role in the pleasurable perception of sad music, as the levels of the hormone increase when a person feels sad, producing a consoling psychological effect. [ 24 ]


The primary function of prolactin in  fish  is  osmoregulation , [ 25 ]  i.e., controlling the movement of water and salts between the tissues of the fish and the surrounding water. Like mammals, however, prolactin in fish also has reproductive functions, including promoting sexual maturation and inducing breeding cycles, as well as brooding and parental care. [ 26 ]  In the South American  discus , prolactin may also regulate the production of a skin secretion that provides food for larval  fry . [ 27 ]  An increase in brooding behaviour caused by prolactin has been reported in  hens . [ 28 ]


Prolactin and  its receptor  are expressed in the skin, specifically in the hair follicles, where they regulate hair growth and moulting in an  autocrine  fashion. [ 29 ] [ 30 ]  Elevated levels of prolactin can inhibit hair growth, [ 31 ]  and knock-out  mutations  in the prolactin gene cause increased hair length in cattle [ 32 ]  and mice. [ 30 ]  Conversely, mutations in the prolactin receptor can cause reduced hair growth, resulting in the "slick" phenotype in cattle. [ 32 ] [ 33 ]  Additionally, prolactin delays hair regrowth in mice. [ 34 ]


Analogous to its effects on hair growth and shedding in mammals, prolactin in birds controls the  moulting  of feathers, [ 35 ]  as well as the age at onset of feathering in both turkeys and chickens. [ 36 ]   Pigeons ,  flamingos  and male  emperor penguins  feed their young a cheese-like secretion from the upper digestive tract called  crop milk , whose production is regulated by prolactin. [ 37 ] [ 38 ]


In rodents,  pseudopregnancy  can occur when a female is mated with a sterile male. This mating can cause bi-daily surges of prolactin which would normally occur in rodent pregnancy. [ 39 ]  Prolactin surges initiate the secretion of progesterone which maintains pregnancy and hence can initiate pseudopregnancy. The false maintenance of pregnancy exhibits the outward physical symptoms of pregnancy, in the absence of a foetus. [ 40 ]


Prolactin receptor activation is essential for normal  mammary gland  development during  puberty  in mice. [ 41 ]  Adult virgin female prolactin receptor  knockout mice  have much smaller and less developed mammary glands than their  wild-type  counterparts. [ 41 ]  Prolactin and prolactin receptor signaling are also essential for maturation of the mammary glands during pregnancy in mice. [ 41 ]


In humans, prolactin is produced at least in the anterior pituitary,  decidua ,  myometrium , breast,  lymphocytes ,  leukocytes  and  prostate . [ 42 ] [ 43 ]


Pituitary prolactin is controlled by the  Pit-1   transcription factor , which binds to the gene at several sites including a proximal promoter. [ 43 ]  This promoter is inhibited by dopamine and stimulated by estrogens, neuropeptides, and growth factors. [ 44 ]  Estrogens can also suppress dopamine.


Interaction with neuropeptides is still a matter of active research: no specific  prolactin-releasing hormone  has been identified. It is known that mice react to both  VIP  and  TRH , but humans seem to only react to TRH. There are  prolactin-releasing peptides  that work  in vitro , but whether they deserve their name has been questioned.  Oxytocin  does not play a large role. Mice without a posterior pituitary do not raise their prolactin levels even with suckling and oxytocin injection, but scientists have yet to identify which specific hormone produced by this region is responsible. [ 45 ]


In birds (turkeys), VIP is a powerful prolactin-releasing factor, while  peptide histidine isoleucine  has almost no effect. [ 46 ]


Extrapituitary prolactin is controlled by a superdistal promoter, located 5.8 kb upstream of the pituitary start site. The promoter does not react to dopamine, estrogens, or TRH. Instead, it is stimulated by  cAMP . Responsiveness to cAMP is mediated by an imperfect cAMP–responsive element and two CAAT/enhancer binding proteins (C/EBP). [ 43 ]   Progesterone  upregulates prolactin synthesis in the  endometrium  but decreases it in  myometrium  and breast glandular tissue. [ 47 ]


Breast and other tissues may express the Pit-1 promoter in addition to the distal promoter.  Oct-1  appears able to substitute for Pit-1 in activating the promoter in breast cancer cells. [ 45 ]


Extrapituitary production of prolactin is thought to be special to humans and primates and may serve mostly tissue-specific  paracrine  and  autocrine  purposes. It has been hypothesized that in vertebrates such as mice a similar tissue-specific effect is achieved by a large family of prolactin-like proteins controlled by at least 26 paralogous  PRL  genes not present in primates. [ 43 ]


Prolactin follows  diurnal  and  ovulatory  cycles. Prolactin levels peak during REM sleep and in the early morning. Many mammals experience a seasonal cycle. [ 38 ]


During  pregnancy , high circulating concentrations of estrogen and progesterone increase prolactin levels by 10- to 20-fold. Estrogen and progesterone inhibit the stimulatory effects of prolactin on milk production. The abrupt drop of estrogen and progesterone levels following delivery allow prolactin—which temporarily remains high—to induce lactation. [ 48 ]


Sucking on the nipple offsets the fall in prolactin as the internal stimulus for them is removed. The sucking activates mechanoreceptors in and around the nipple. These signals are carried by nerve fibers through the spinal cord to the  hypothalamus , where changes in the electrical activity of neurons that regulate the  pituitary gland  increase prolactin secretion. The suckling stimulus also triggers the release of  oxytocin  from the  posterior pituitary gland , which triggers milk let-down: Prolactin controls milk production (lactogenesis) but not the milk-ejection reflex; the rise in prolactin fills the breast with milk in preparation for the next feed. The posterior pituitary produces a yet-unidentified hormone that causes prolactin production. [ 45 ]


In usual circumstances, in the absence of  galactorrhea , lactation ceases within one or two weeks following the end of  breastfeeding .


Levels can rise after exercise, high-protein meals, minor surgical procedures, [ 49 ]  following  epileptic seizures [ 50 ]  or due to physical or emotional  stress . [ 51 ] [ 52 ]  In a study on female volunteers under hypnosis, prolactin surges resulted from the evocation, with rage, of humiliating experiences, but not from the fantasy of nursing. [ 52 ]  Stress-induced PRL changes are not linked to the posterior pituitary in rodents. [ 45 ]


Hypersecretion is more common than hyposecretion. Hyperprolactinemia is the most frequent abnormality of the anterior pituitary tumors, termed  prolactinomas . Prolactinomas may disrupt the  hypothalamic-pituitary-gonadal axis  as prolactin tends to suppress the secretion of gonadotropin-releasing hormone from the hypothalamus and in turn decreases the secretion of  follicle-stimulating hormone  and  luteinizing hormone  from the anterior pituitary, therefore disrupting the  ovulatory cycle . [ 53 ]  Such hormonal changes may manifest as  amenorrhea  and infertility in females as well as  erectile dysfunction  in males. [ 54 ] [ 7 ]  Inappropriate lactation ( galactorrhoea ) is another important clinical sign of prolactinomas.


The structure of prolactin is similar to that of  growth hormone  and  placental lactogen . The molecule is folded due to the activity of three  disulfide bonds . Significant heterogeneity of the molecule has been described, thus  bioassays  and  immunoassays  can give different results due to differing  glycosylation ,  phosphorylation  and  sulfation , as well as degradation. The non-glycosylated form of prolactin is the dominant form that is secreted by the  pituitary gland . [ 11 ]


The three different sizes of prolactin are:


The levels of larger ones are somewhat higher during the early  postpartum period . [ 58 ]


Prolactin receptors are present in the  mammillary glands ,  ovaries , pituitary glands, heart, lung,  thymus ,  spleen , liver, pancreas,  kidney ,  adrenal gland ,  uterus ,  skeletal muscle , skin and areas of the  central nervous system . [ 59 ]  When prolactin binds to the receptor, it causes it to  dimerize  with another prolactin receptor. This results in the activation of  Janus kinase 2 , a  tyrosine kinase  that initiates the  JAK-STAT pathway . Activation also results in the activation of  mitogen-activated protein kinases  and  Src kinase . [ 59 ]


Human prolactin receptors are insensitive to mouse prolactin. [ 60 ]


Prolactin levels may be checked as part of a  sex hormone  workup, as elevated prolactin secretion can suppress the secretion of follicle stimulating hormone and gonadotropin-releasing hormone, leading to  hypogonadism  and sometimes causing  erectile dysfunction . [ 61 ]


Prolactin levels may be of some use in distinguishing  epileptic seizures  from  psychogenic non-epileptic seizures . The serum prolactin level usually rises following an epileptic seizure. [ 62 ]


The serum concentration of prolactin can be given in  mass concentration  ( μg / L  or  ng / mL ),  molar concentration  ( nmol /L or  pmol /L), or  international units  (typically mIU/L). The current IU is calibrated against the third International Standard for Prolactin, IS 84/500. [ 63 ] [ 64 ]  Reference ampoules of IS 84/500 contain "approximately" 2.5 μg of  lyophilized  human prolactin [ 65 ]  and have been assigned an activity of 0.053 International Units by calibrating against the previous standard. [ 63 ] [ 64 ]  Measurements can be converted into mass units using this ratio of grams to IUs to obtain an equivalent in relationship to the contents of IS 84/500; [ 66 ]  prolactin concentrations expressed in mIU/L can be converted to μg/L of IS 84/500 equivalent by dividing by 21.2. Previous standards had other ratios in relation to their potency on the assay measurement. For example, the previous IS (83/562) had a potency of 27.0 mIU per μg. [ 67 ] [ 68 ] [ 69 ] [ 70 ]


The first  International Reference Preparation  (or IRP) of human Prolactin for Immunoassay was established in 1978 (75/504 1st IRP for human prolactin) at a time when purified human prolactin was in short supply. [ 66 ] [ 67 ]  Previous standards relied on prolactin from animal sources. [ 70 ]  Purified human prolactin was scarce, heterogeneous, unstable, and difficult to characterize. A preparation labeled 81/541 was distributed by the  WHO Expert Committee on Biological Standardization  without official status and given the assigned value of 50 mIU/ampoule based on an earlier collaborative study. [ 66 ] [ 68 ]  It was determined that this preparation behaved anomalously in certain  immunoassays  and was not suitable as an IS. [ 66 ]


Three different human pituitary extracts containing prolactin were subsequently obtained as candidates for an IS. These were distributed into ampoules coded 83/562, 83/573, and 84/500. [ 63 ] [ 64 ] [ 66 ] [ 69 ]  Collaborative studies involving 20 different laboratories found little difference between these three preparations. 83/562 appeared to be the most stable. This preparation was largely free of dimers and  polymers  of prolactin. On the basis of these investigations, 83/562 was established as the Second IS for human prolactin. [ 69 ]  Once stocks of these ampoules were depleted, 84/500 was established as the Third IS for human prolactin. [ 63 ] [ 66 ]


84/500 has nearly run out and in 2016 replacement was proposed. The new 83/573 contains 67.2 mIU per ampoule when calibrated against the third IS and contains 1.002 g of human pituitary extract each (which is then lyophilized). Each ampoule contains approximately 3.2 μg of prolactin. The  assigned value  will be 67 mIU per ampoule. If a fifth IS is needed, it will likely be based on  recombinant protein , as WHO has not received any further donations of human pituitary extracts. [ 71 ]


General guidelines for diagnosing prolactin excess ( hyperprolactinemia ) define the upper threshold of normal prolactin at 25 μg/L for women and 20 μg/L for men. [ 59 ]  Similarly, guidelines for diagnosing prolactin deficiency ( hypoprolactinemia ) are defined as prolactin levels below 3 μg/L in women [ 72 ] [ 73 ]  and 5 μg/L in men. [ 74 ] [ 75 ] [ 76 ]  However, different assays and methods for measuring prolactin are employed by different laboratories and as such the  serum reference range  for prolactin is often determined by the laboratory performing the measurement. [ 59 ] [ 77 ]  Furthermore, prolactin levels vary according to factors as age, [ 78 ]  sex, [ 78 ]   menstrual cycle  stage [ 78 ]  and pregnancy. [ 78 ]  The circumstances surrounding a given prolactin measurement (assay, patient condition, etc.) must therefore be considered before the measurement can be accurately interpreted. [ 59 ]


The following chart illustrates the variations seen in normal prolactin measurements across different populations. Prolactin values were obtained from specific control groups of varying sizes using the IMMULITE  assay . [ 78 ]


The following table illustrates variability in reference ranges of serum prolactin between some commonly used assay methods (as of 2008), using a control group of healthy health care professionals (53 males, age 20–64 years, median 28 years; 97 females, age 19–59 years, median 29 years) in  Essex , England: [ 77 ]


An example of the use of the above table is, if using the Centaur assay to estimate prolactin values in μg/L for females, the mean is 168 mIU/L (7.92 μg/L) and the reference range is 71–348 mIU/L (3.35–16.4 μg/L).


Hyperprolactinaemia , or excess serum prolactin, is associated with  hypoestrogenism ,  anovulatory   infertility ,  oligomenorrhoea ,  amenorrhoea , unexpected  lactation  and loss of  libido  in women and  erectile dysfunction  and loss of libido in men. [ 80 ]


Causes of Elevated Prolactin Levels


Physiological


Pharmacological


Pathological


Hypoprolactinemia , or serum prolactin deficiency, is associated with ovarian dysfunction in women, [ 72 ] [ 73 ]  and  arteriogenic   erectile dysfunction ,  premature ejaculation , [ 74 ]   oligozoospermia ,  asthenospermia , hypofunction of  seminal vesicles  and  hypoandrogenism [ 75 ]  in men. In one study, normal sperm characteristics were restored when prolactin levels were raised to normal values in hypoprolactinemic men. [ 76 ]


Hypoprolactinemia can result from  hypopituitarism , excessive  dopaminergic  action in the  tuberoinfundibular pathway  and ingestion of  D 2  receptor   agonists  such as  bromocriptine . [ citation needed ]


Prolactin is available commercially for use in other animals, but not in humans. [ 81 ]  It is used to stimulate lactation in animals. [ 81 ]  The  biological half-life  of prolactin in humans is around 15–20 minutes. [ 82 ]  The D 2  receptor is involved in the regulation of prolactin secretion, and agonists of the receptor such as  bromocriptine  and  cabergoline  decrease prolactin levels while antagonists of the receptor such as  domperidone ,  metoclopramide ,  haloperidol ,  risperidone , and  sulpiride  increase prolactin levels. [ 83 ]  D 2  receptor antagonists like domperidone, metoclopramide, and sulpiride are used as  galactogogues  to increase prolactin secretion in the pituitary gland and induce lactation in humans. [ 84 ]


Thyroid-stimulating hormone  (also known as  thyrotropin ,  thyrotropic hormone , or abbreviated  TSH ) is a  pituitary hormone  that stimulates the  thyroid  gland to produce  thyroxine  (T 4 ), and then  triiodothyronine  (T 3 ) which stimulates the metabolism of almost every tissue in the body. [ 1 ]  It is a  glycoprotein  hormone produced by  thyrotrope  cells in the  anterior pituitary gland , which regulates the endocrine function of the thyroid. [ 2 ] [ 3 ]


TSH (with a half-life of about an hour) stimulates the thyroid gland to secrete the hormone  thyroxine  (T 4 ), which has only a slight effect on metabolism. T 4  is converted to  triiodothyronine  (T 3 ), which is the active hormone that stimulates metabolism. About 80% of this conversion is in the liver and other organs, and 20% in the thyroid itself. [ 1 ]


TSH is secreted throughout life but particularly reaches high levels during the periods of rapid growth and development, as well as in response to stress.


The  hypothalamus , in the base of the brain, produces  thyrotropin-releasing hormone  (TRH). TRH stimulates the anterior  pituitary gland  to produce TSH.


Somatostatin  is also produced by the hypothalamus, and has an opposite effect on the pituitary production of TSH, decreasing or inhibiting its release.


The concentration of thyroid hormones (T 3  and T 4 ) in the blood regulates the pituitary release of TSH; when  T 3  and T 4  concentrations are low, the production of TSH is increased, and, conversely, when T 3  and T 4  concentrations are high,  TSH production is decreased. This is an example of a  negative feedback  loop. [ 5 ]  Any inappropriateness of measured values, for instance a low-normal TSH together with a low-normal T 4  may signal tertiary (central) disease and a TSH to TRH pathology. Elevated reverse T 3  (RT 3 ) together with low-normal TSH and low-normal T 3 , T 4  values, which is regarded as indicative for euthyroid sick syndrome, may also have to be investigated for chronic subacute thyroiditis (SAT) with output of subpotent hormones. Absence of antibodies in patients with diagnoses of an autoimmune thyroid in their past would always be suspicious for development to SAT even in the presence of a normal TSH because there is no known recovery from autoimmunity.


For clinical interpretation of laboratory results it is important to acknowledge that TSH is released in a  pulsatile manner [ 6 ] [ 7 ] [ 8 ]  resulting in both circadian and ultradian rhythms of its serum concentrations. [ 9 ]


TSH is a glycoprotein and consists of two subunits, the  alpha  and the  beta  subunit.


The TSH receptor is found mainly on  thyroid follicular cells . [ 12 ]  Stimulation of the receptor increases T 3  and T 4  production and secretion. This occurs through stimulation of six steps in thyroid hormone synthesis: (1) Up-regulating the activity of the  sodium-iodide symporter  (NIS) on the basolateral membrane of thyroid follicular cells, thereby increasing intracellular concentrations of iodine (iodine trapping). (2) Stimulating iodination of thyroglobulin in the follicular lumen, a precursor protein of thyroid hormone. (3) Stimulating the conjugation of iodinated tyrosine residues. This leads to the formation of thyroxine (T 4 ) and  triiodothyronine  (T 3 ) that remain attached to the thyroglobulin protein. (4) Increased endocytocis of the iodinated thyroglobulin protein across the apical membrane back into the follicular cell. (5) Stimulation of proteolysis of iodinated thyroglobulin to form free thyroxine (T 4 ) and triiodothyronine (T 3 ). (6) Secretion of thyroxine (T 4 ) and triiodothyronine (T 3 ) across the basolateral membrane of follicular cells to enter the circulation. This occurs by an unknown mechanism. [ 13 ]


Stimulating antibodies to the TSH receptor mimic TSH and cause  Graves' disease . In addition, hCG shows some cross-reactivity to the TSH receptor and therefore can stimulate production of thyroid hormones. In pregnancy, prolonged high concentrations of hCG can produce a transient condition termed gestational  hyperthyroidism . [ 14 ]  This is also the mechanism of  trophoblastic tumors  increasing the production of thyroid hormones. [ citation needed ]


Reference ranges  for TSH may vary slightly, depending on the method of analysis, and do not necessarily equate to cut-offs for diagnosing thyroid dysfunction. In the UK, guidelines issued by the  Association for Clinical Biochemistry  suggest a reference range of 0.4–4.0 μIU/mL (or mIU/L). [ 15 ]  The   National Academy of Clinical Biochemistry  (NACB) stated that it expected the reference range for adults to be reduced to 0.4–2.5 μIU/mL, because research had shown that adults with an initially measured TSH level of over 2.0 μIU/mL had "an increased  odds ratio  of developing  hypothyroidism  over the [following] 20 years, especially if thyroid antibodies were elevated". [ 16 ]


TSH concentrations in children are normally higher than in adults. In 2002, the NACB recommended age-related reference limits starting from about 1.3 to 19 μIU/mL for normal-term infants at birth, dropping to 0.6–10 μIU/mL at 10 weeks old, 0.4–7.0 μIU/mL at 14 months and gradually dropping during childhood and puberty to adult levels, 0.3–3.0 μIU/mL. [ 17 ] : Section 2


TSH concentrations are measured as part of a thyroid function test in patients suspected of having an excess (hyperthyroidism) or deficiency (hypothyroidism) of thyroid hormones. Interpretation of the results depends on both the TSH and T 4  concentrations. In some situations measurement of T 3  may also be useful.


A TSH assay is now also the recommended screening tool for thyroid disease.  Recent advances in increasing the sensitivity of the TSH assay make it a better screening tool than free T 4 . [ 3 ]


The  therapeutic target range  TSH level for patients on treatment ranges between 0.3 and 3.0 μIU/mL. [ 18 ]


For hypothyroid patients on thyroxine, measurement of TSH alone is generally considered sufficient. An increase in TSH above the normal range indicates under-replacement or poor compliance with therapy. A significant reduction in TSH suggests over-treatment. In both cases, a change in dose may be required. A low or low-normal TSH value may also signal pituitary disease in the absence of replacement. [ citation needed ]


For hyperthyroid patients, both TSH and T 4  are usually monitored. In pregnancy, TSH measurements do not seem to be a good marker for the well-known association of maternal thyroid hormone availability with offspring neurocognitive development. [ 19 ]


TSH distribution progressively shifts toward higher concentrations with age. [ 20 ]


Synthetic  recombinant  human TSH alpha (rhTSHα or simply rhTSH) or thyrotropin alfa ( INN ) is manufactured by  Genzyme Corp  under the trade name  Thyrogen . [ 30 ] [ 31 ]  It is used to manipulate endocrine function of thyroid-derived cells, as part of the diagnosis and treatment of  thyroid cancer . [ 32 ] [ 28 ]


A Cochrane review compared treatments using recombinant human thyrotropin-aided radioactive iodine to radioactive iodine alone. [ 33 ]  In this review it was found that the recombinant human thyrotropin-aided radioactive iodine appeared to lead to a greater reduction in thyroid volume at the increased risk of hypothyroidism. [ 33 ]  No conclusive data on changes in quality of life with either treatments were found. [ 33 ]


In 1916, Bennett M. Allen and Philip E. Smith found that the pituitary contained a thyrotropic substance. [ 34 ]  The first standardised purification protocol for this thyrotropic hormone was described by  Charles George Lambie  and  Victor Trikojus , working at the  University of Sydney  in 1937. [ 35 ]


Antagonists:   Pegvisomant


Tropic hormones  are  hormones  that have other  endocrine glands  as their target. Most tropic hormones are produced and secreted by the  anterior pituitary . [ 1 ] : 719   The  hypothalamus  secretes tropic hormones that target the anterior pituitary, and the  thyroid gland  secretes  thyroxine , which targets the  hypothalamus  and therefore can be considered a tropic hormone. [ 2 ]


The term  tropic  is from  Ancient Greek   τροπικός  ( tropikós ), in the sense "of or pertaining to a turn or change", meaning "causing a change, affecting"; this is the same origin as  tropic  and  trope .  This should not be confused with  tro ph ic ,  as in similar-sounding  trophic hormone  – the words and concepts are both unrelated. [ 3 ]  Tropic hormones are contrasted with  non-tropic hormones , which directly stimulate target cells.


Tropic hormones from the anterior pituitary include:


In turn, the  hypothalamus  controls the release of hormones from the anterior pituitary by secreting a class of hypothalamic  neurohormones  called  releasing and release-inhibiting hormones —which are released to the  hypothalamo-hypophyseal portal system  and act on the anterior pituitary. [ 1 ] : 720–721


In vitro fertilisation  ( IVF ) is a process of  fertilisation  in which an  egg  is combined with  sperm   in vitro  ("in glass"). The process involves monitoring and stimulating a woman's  ovulatory process , then removing an ovum or ova (egg or eggs) from her  ovaries  and enabling a man's sperm to fertilise them in a culture medium in a laboratory. After a fertilised egg ( zygote ) undergoes  embryo culture  for 2–6 days, it is  transferred  by  catheter  into the  uterus , with the intention of establishing a successful  pregnancy .


IVF is a type of  assisted reproductive technology  used to treat  infertility , enable  gestational surrogacy , and, in combination with  pre-implantation genetic testing , avoid the transmission of abnormal genetic conditions. When a fertilised egg from egg and sperm donors  implants  in the uterus of a genetically unrelated surrogate, the resulting child is also genetically unrelated to the surrogate. Some countries have banned or otherwise regulated the availability of IVF treatment, giving rise to  fertility tourism . Financial cost and age may also restrict the availability of IVF as a means of carrying a healthy pregnancy to term.


In July 1978,  Louise Brown  was the first child successfully born after her mother received IVF treatment. [ 1 ]  Brown was born as a result of natural-cycle IVF, where no stimulation was made. The procedure took place at Dr Kershaw's Cottage Hospital (later Dr Kershaw's Hospice) in  Royton , Oldham, England.  Robert Edwards  was awarded the  Nobel Prize in Physiology or Medicine  in 2010. (The physiologist co-developed the treatment together with  Patrick Steptoe  and embryologist  Jean Purdy  but the latter two were not eligible for consideration as they had died: the Nobel Prize is not awarded posthumously.) [ 2 ] [ 3 ]


When assisted by  egg donation  and IVF, many women who have reached  menopause , have infertile partners, or have idiopathic female-fertility issues, can still become pregnant. After the IVF treatment, some couples get pregnant without any fertility treatments. [ 4 ]  In 2023, it was estimated that twelve million children had been born worldwide using IVF and other assisted reproduction techniques. [ 5 ]  A 2019 study that evaluated the use of 10 adjuncts with IVF (screening hysteroscopy, DHEA, testosterone, GH, aspirin, heparin, antioxidants, seminal plasma and PRP) suggested that (with the exception of hysteroscopy) these adjuncts should be avoided until there is more evidence to show that they are safe and effective. [ 6 ]


The Latin term  in vitro , meaning "in glass", is used because early biological experiments involving cultivation of tissues outside the living organism were carried out in glass containers, such as beakers, test tubes, or Petri dishes. The modern scientific term "in vitro" refers to any biological procedure that is performed outside the organism in which it would normally have occurred, to distinguish it from an  in vivo  procedure (such as  in vivo fertilisation ), where the tissue remains inside the living organism in which it is normally found.


A colloquial term for babies conceived as the result of IVF, "test tube babies", refers to the tube-shaped containers of glass or plastic resin, called  test tubes , that are commonly used in chemistry and biology labs. However, IVF is usually performed in  Petri dishes , which are both wider and shallower and often used to cultivate cultures.


IVF is a form of  assisted reproductive technology .


The first successful birth of a child after IVF treatment,  Louise Brown , occurred in 1978. Louise Brown was born as a result of natural cycle IVF where no stimulation was made. The procedure took place at Dr Kershaw's Cottage Hospital (now Dr Kershaw's Hospice) in  Royton , Oldham, England.  Robert G. Edwards , the physiologist who co-developed the treatment, was awarded the  Nobel Prize in Physiology or Medicine  in 2010. His co-workers,  Patrick Steptoe  and  Jean Purdy , were not eligible for consideration as the Nobel Prize is not awarded posthumously. [ 2 ] [ 3 ]


The second successful birth of a 'test tube baby' occurred in India on October 3, 1978, just 67 days after Louise Brown was born. The girl, named Durga, was conceived in vitro using a method developed independently by  Subhash Mukhopadhyay , a physician and researcher from  Hazaribag . Mukhopadhyay had been performing experiments on his own with primitive instruments and a household refrigerator. [ 7 ]  However, state authorities prevented him from presenting his work at scientific conferences, [ 8 ]  and it was many years before Mukhopadhyay's contribution was acknowledged in works dealing with the subject. [ 9 ] [ better source needed ]


Adriana Iliescu  held the record as the oldest woman to give birth using IVF and a donor egg, when she gave birth in 2004 at the age of 66, a record passed in 2006. After the IVF treatment some couples are able to get pregnant without any fertility treatments. [ 4 ]  In 2018 it was estimated that eight million children had been born worldwide using IVF and other assisted reproduction techniques. [ 10 ]


IVF may be used to overcome  female infertility  when it is due to problems with the  fallopian tubes , making in vivo fertilisation difficult. It can also assist in  male infertility , in those cases where there is a defect in  sperm quality ; in such situations  intracytoplasmic sperm injection  (ICSI) may be used, where a sperm cell is injected directly into the egg cell. This is used when sperm has difficulty penetrating the egg. ICSI is also used when sperm numbers are very low. When indicated, the use of ICSI has been found to increase the success rates of IVF.


According to UK's  National Institute for Health and Care Excellence  (NICE) guidelines, IVF treatment is appropriate in cases of unexplained infertility for people who have not conceived after 2 years of regular unprotected sexual intercourse. [ 11 ]


In people with  anovulation , it may be an alternative after 7–12 attempted cycles of  ovulation induction , since the latter is expensive and more easy to control. [ 12 ]


IVF success rates are the percentage of all IVF procedures that result in favourable outcomes. Depending on the type of calculation used, this outcome may represent the number of confirmed pregnancies, called the  pregnancy rate , or the number of live births, called the  live birth rate . Due to advances in reproductive technology, live birth rates by cycle five of IVF have increased from 76% in 2005 to 80% in 2010, despite a reduction in the number of embryos being transferred (which decreased the multiple birth rate from 25% to 8%). [ 13 ]


The success rate depends on variable factors such as age of the woman, cause of infertility, embryo status, reproductive history, and lifestyle factors. Younger candidates of IVF are more likely to get pregnant. People older than 41 are more likely to get pregnant with a donor egg. [ 14 ]  People who have been previously pregnant are in many cases more successful with IVF treatments than those who have never been pregnant. [ 14 ]


The live birth rate is the percentage of all IVF cycles that lead to a live birth. This rate does not include  miscarriage  or  stillbirth ;  multiple-order births, such as twins and triplets, are counted as one pregnancy.


A 2021 summary compiled by the Society for Assisted Reproductive Technology (SART) which reports the average IVF success rates in the United States per age group using non-donor eggs compiled the following data: [ 15 ]


In 2006, Canadian clinics reported a live birth rate of 27%. [ 16 ]  Birth rates in younger patients were slightly higher, with a success rate of 35.3% for those 21 and younger, the youngest group evaluated. Success rates for older patients were also lower and decrease with age, with 37-year-olds at 27.4% and no live births for those older than 48, the oldest group evaluated. [ 17 ]  Some clinics exceeded these rates, but it is impossible to determine if that is due to superior technique or patient selection, since it is possible to artificially increase success rates by refusing to accept the most difficult patients or by steering them into  oocyte  donation cycles (which are compiled separately). Further, pregnancy rates can be increased by the placement of several embryos at the risk of increasing the chance for multiples.


Because not each IVF cycle that is started will lead to oocyte retrieval or embryo transfer, reports of live birth rates need to specify the denominator, namely IVF cycles started, IVF retrievals, or embryo transfers. The SART summarised 2008–9 success rates for US clinics for fresh embryo cycles that did not involve donor eggs and gave live birth rates by the age of the prospective mother, with a peak at 41.3% per cycle started and 47.3% per embryo transfer for patients under 35 years of age.


IVF attempts in multiple cycles result in increased cumulative live birth rates. Depending on the demographic group, one study reported 45% to 53% for three attempts, and 51% to 71% to 80% for six attempts. [ 18 ]


According to the 2021 National Summary Report compiled by the Society for Assisted Reproductive Technology (SART), the mean number of embryos transfers for patients achieving live birth go as follows: [ 19 ]


Effective from 15 February 2021 the majority of Australian IVF clinics publish their individual success rate online via YourIVFSuccess.com.au. This site also contains a predictor tool. [ 20 ]


Pregnancy rate may be defined in various ways. In the United States, SART and the  Centers for Disease Control  (and appearing in the table in the Success Rates section above) include statistics on positive pregnancy test and clinical pregnancy rate.


The 2019 summary compiled by the SART the following data for non-donor eggs (first embryo transfer) in the United States: [ 21 ]


In 2006, Canadian clinics reported an average pregnancy rate of 35%. [ 16 ]  A French study estimated that 66% of patients starting IVF treatment finally succeed in having a child (40% during the IVF treatment at the centre and 26% after IVF discontinuation). Achievement of having a child after IVF discontinuation was mainly due to  adoption  (46%) or  spontaneous pregnancy  (42%). [ 22 ]


According to a study done by the  Mayo Clinic ,  miscarriage  rates for IVF are somewhere between 15 and 25% for those under the age of 35. [ 23 ]  In naturally conceived pregnancies, the rate of miscarriage is between 10 and 20% for those under the age of 35. [ 24 ]  Risk of miscarriage, regardless of the method of conception, does increase with age. [ 23 ]


The main potential factors that influence pregnancy (and live birth) rates in IVF have been suggested to be  maternal age , duration of infertility or subfertility,  bFSH  and number of oocytes, all reflecting  ovarian function . [ 25 ]  Optimal age is 23–39 years at time of treatment. [ 26 ]


Biomarkers  that affect the pregnancy chances of IVF include:


Other  determinants  of outcome of IVF include:


Aspirin is sometimes prescribed to people for the purpose of increasing the chances of conception by IVF, but as of 2016 [update]  there was no evidence to show that it is safe and effective. [ 42 ] [ 43 ]


A 2013  review  and  meta analysis  of  randomised controlled trials  of  acupuncture  as an  adjuvant therapy  in IVF found no overall benefit, and concluded that an apparent benefit detected in a subset of published trials where the control group (those not using acupuncture) experienced a lower than average rate of pregnancy requires further study, due to the possibility of  publication bias  and other factors. [ 44 ]


A  Cochrane review  came to the result that  endometrial  injury performed in the month prior to ovarian induction appeared to increase both the live birth rate and clinical pregnancy rate in IVF compared with no endometrial injury. There was no evidence of a difference between the groups in miscarriage, multiple pregnancy or bleeding rates. Evidence suggested that endometrial injury on the day of oocyte retrieval was associated with a lower live birth or ongoing pregnancy rate. [ 40 ]


Intake of  antioxidants  (such as  N-acetyl-cysteine ,  melatonin ,  vitamin A ,  vitamin C ,  vitamin E ,  folic acid ,  myo-inositol ,  zinc  or  selenium ) has not been associated with a significantly increased  live birth rate  or clinical  pregnancy rate  in IVF according to  Cochrane reviews . [ 40 ]  The review found that oral antioxidants given to the sperm donor with male factor or unexplained subfertility may improve live birth rates, but more evidence is needed. [ 40 ]


A  Cochrane review  in 2015 came to the result that there is no evidence identified regarding the effect of preconception lifestyle advice on the chance of a live birth outcome. [ 40 ]


Theoretically, IVF could be performed by collecting the contents from the fallopian tubes or uterus after natural ovulation, mixing it with  sperm , and reinserting the fertilised ova into the uterus. However, without additional techniques, the chances of pregnancy would be extremely small. The additional techniques that are routinely used in IVF include  ovarian hyperstimulation  to generate multiple eggs, ultrasound-guided  transvaginal oocyte retrieval  directly from the ovaries, co-incubation of eggs and sperm, as well as culture and selection of resultant embryos before  embryo transfer  into a uterus.


Ovarian hyperstimulation is the stimulation to induce development of multiple follicles of the ovaries. It should start with response prediction based on factors such as age,  antral follicle count  and level of  anti-Müllerian hormone . [ 45 ]  The resulting prediction (e.g. poor or hyper-response to ovarian hyperstimulation) determines the protocol and dosage for ovarian hyperstimulation. [ 45 ]


Ovarian hyperstimulation also includes suppression of spontaneous ovulation, for which two main methods are available: Using a (usually longer)  GnRH agonist  protocol or a (usually shorter)  GnRH antagonist  protocol. [ 45 ]  In a standard long GnRH agonist protocol the day when hyperstimulation treatment is started and the expected day of later oocyte retrieval can be chosen to conform to personal choice, while in a GnRH antagonist protocol it must be adapted to the spontaneous onset of the previous menstruation. On the other hand, the GnRH antagonist protocol has a lower risk of  ovarian hyperstimulation syndrome  (OHSS), which is a life-threatening complication. [ 45 ]


For the ovarian hyperstimulation in itself, injectable  gonadotropins  (usually  FSH  analogues) are generally used under close monitoring. Such monitoring frequently checks the  estradiol  level and, by means of  gynecologic ultrasonography , follicular growth. Typically approximately 10 days of injections will be necessary.


When stimulating ovulation after suppressing endogenous secretion, it is necessary to supply exogenous gonadotropines. The most common one is the  human menopausal gonadotropin  (hMG), which is obtained by donation of menopausal women. Other  pharmacological preparations  are FSH+LH or coripholitropine alpha.


There are several methods termed natural cycle IVF: [ 46 ]


IVF using no drugs for ovarian hyperstimulation was the method for the conception of  Louise Brown . This method can be successfully used when people want to avoid taking ovarian stimulating drugs with its associated side-effects.  HFEA  has estimated the  live birth rate  to be approximately 1.3% per IVF cycle using no hyperstimulation drugs for women  aged between 40 and 42. [ 48 ]


Mild IVF [ 49 ]  is a method where a small dose of ovarian stimulating drugs are used for a short duration during a natural menstrual cycle aimed at producing 2–7 eggs and creating healthy embryos. This method appears to be an advance in the field to reduce complications and side-effects for women, and it is aimed at quality, and not quantity of eggs and embryos. One study comparing a mild treatment (mild ovarian stimulation with GnRH antagonist co-treatment combined with  single embryo transfer ) to a standard treatment (stimulation with a  GnRH agonist  long-protocol and transfer of two embryos) came to the result that the proportions of cumulative pregnancies that resulted in term  live birth  after 1 year were 43.4% with mild treatment and 44.7% with standard treatment. [ 50 ]  Mild IVF can be cheaper than conventional IVF and with a significantly reduced risk of  multiple gestation  and  OHSS . [ 51 ]


When the ovarian follicles have reached a certain degree of development,  induction of final oocyte maturation  is performed, generally by an injection of  human chorionic gonadotropin  (hCG). Commonly, this is known as the "trigger shot." [ 52 ]  hCG acts as an analogue of  luteinising hormone , and ovulation would occur between 38 and 40 hours after a single HCG injection, [ 53 ]  but the egg retrieval is performed at a time usually between 34 and 36 hours after hCG injection, that is, just prior to when the follicles would rupture. This avails for scheduling the egg retrieval procedure at a time where the eggs are fully mature. HCG injection confers a risk of  ovarian hyperstimulation syndrome . Using a  GnRH agonist  instead of hCG eliminates most of the risk of ovarian hyperstimulation syndrome, but with a reduced delivery rate if the embryos are transferred fresh. [ 54 ]   For this reason, many centers will freeze all oocytes or embryos following agonist trigger.


The eggs are retrieved from the patient using a transvaginal technique called  transvaginal  ultrasound aspiration involving an ultrasound-guided needle being injected through follicles upon collection. Through this needle, the oocyte and follicular fluid are aspirated and the follicular fluid is then passed to an embryologist to identify ova. It is common to remove between ten and thirty eggs. The retrieval process, which lasts approximately 20 to 40 minutes, is performed under  conscious sedation  or  general anesthesia  to ensure patient comfort. Following optimal follicular development, the eggs are meticulously retrieved using transvaginal ultrasound guidance with the aid of a specialised ultrasound probe and a fine needle aspiration technique. The follicular fluid, containing the retrieved eggs, is expeditiously transferred to the embryology laboratory for subsequent processing. [ 55 ]


In the laboratory, for ICSI treatments, the identified eggs are stripped of surrounding cells (also known as  cumulus cells ) and prepared for  fertilisation . An  oocyte selection  may be performed prior to fertilisation to select eggs that can be fertilised, as it is required they are in metaphase II. There are cases in which if oocytes are in the metaphase I stage, they can be kept being cultured so as to undergo a posterior sperm injection. In the meantime,  semen  is prepared for fertilisation by removing inactive cells and seminal fluid in a process called  sperm washing . If semen is being provided by a  sperm donor , it will usually have been prepared for treatment before being frozen and quarantined, and it will be thawed ready for use. [ citation needed ]


The sperm and the egg are incubated together at a ratio of about 75,000:1 in a  culture media  in order for the actual  fertilisation  to take place. A review in 2013 came to the result that a duration of this co-incubation of about 1 to 4 hours results in significantly higher  pregnancy rates  than 16 to 24 hours. [ 56 ]  In most cases, the egg will be fertilised during co-incubation and will show two  pronuclei . In certain situations, such as low sperm count or motility, a single sperm may be injected directly into the egg using  intracytoplasmic sperm injection  (ICSI). The fertilised egg is passed to a special growth medium and left for about 48 hours until the embryo consists of six to eight cells.


In  gamete intrafallopian transfer , eggs are removed from the woman and placed in one of the fallopian tubes, along with the man's sperm. This allows fertilisation to take place inside the woman's body. Therefore, this variation is actually an in vivo fertilisation, not in vitro. [ 57 ] [ 58 ]