The Role of Oxytocin from Birth to Old Age
Jorge D. Flechas M.D., M.P.H., H(MD)
This paper offers an introduction to the hormone oxytocin and its many physiological functions.
Oxytocin (OT) is synthesized as a nine-amino-acid neuropeptide inside the neurons of the hypothalamic periventricular nuclei (PVN) and the supraoptic nuclei (SON). Oxytocin is also produced in peripheral tissues such as the placenta, the corpus luteum, the testes, the heart, the adrenals, the pancreas, and other tissues.
1 The neurons make oxytocin as part of a peptide precursor. By enzyme activity, the prohormone is cleaved and amidated as it is transported down the axon.
2 Oxytocin is attached to a neurophysin I (a transport protein that is stimulated into production by estrogen) and to OT- extended form (OT-X), which is oxytocin with a C-terminal three-amino-acid extension.
3 The prohormone undergoes proteolysis by several convertase enzymes as it travels down the axon.
These enzymes are present in the oxytocin neurosecretory vesicles. By the time the prohormone reaches the terminal end of the axon, oxytocin is released as its nine-amino-acid neuropeptide into the body or into the brain. It has been documented that oxytocin receptors can be found in the brain and that these receptors occur in areas throughout the brain, not just in one region. However, the oxytocin receptors are found in higher concentrations in some areas of the brain, including the amygdala, the hippocampus, the septum, the PVN, the brainstem area, and the posterior dorsal horn cells of the spine.2,4-8 Oxytocin receptors have also been identified in other parts of the body, including the kidney, heart, thymus, pancreas, and adipocytes.1 It is now known that the axons that distribute oxytocin from the PVN and SON go from the hypothalamus to many regions of the brain such as the brainstem and the spinal cord areas.9 Papers have been published documenting that oxytocin modulates neural circuitry for social cognition and fear in humans.10 Oxytocin is known to have antinociceptive and analgesic properties as well as anxiolytic and antidepressant effects, which makes this neuropeptide of interest especially in the field of fibromyalgia research.10 The fact that oxytocin has been found in high concentrations in the posterior dorsal horn cells of the spine suggests that the periventriculo-spinal pathway is particularly related to specific groups of sympathetic and parasympathetic neurons and to the marginal zone, which is involved in the relay of ascending nociceptive information through the spinal thalamic tract.
11 A mother releases oxytocin when she is nursing her child or when she hears the baby crying.12,13 One has to be concerned about the presence of silicone breast implants since the ability of the brain to communicate with the breast tissue is inhibited by nerves that were cut at the time of surgery. Silicone implant surgery often results in a loss of feeling and sensation in the nipples, and the nipples help provide information to the brain for release of oxytocin. The loss of breast tissue that occurs with many breast cancer surgeries also presents concerns as this loss results in the removal of a major pathway for the stimulation of oxytocin production. For years, a decrease in breast milk in lactating mothers has been noted to occur in the presence of stress, anger and fear. An increase in milk production has been seen in the presence of acetylcholine and in the presence of inositol, a carbohydrate alcohol that is found in rice. Oxytocin functions to contract smooth muscle cells by binding to heptahelical G protein receptors. When oxytocin binds to these receptors, inositol triphosphate and diacylglycerol are formed. These compounds increase intracellular calcium and activate protein kinase C (which plays a role in phosphorylating membrane calcium channels), and thereby further increase the levels of intracellular calcium. The increased influx of calcium results in the binding of calcium to calmodulin in muscle cells, which activates myosin, and thus, results in the contraction of endometrial and myoepithelial cells.14
Oxytocin is inhibited by stress, opioid peptides, opioids, fear and anger.10,15-21 Extrauterine actions of oxytocin were first discovered during an early medical conference on oxytocin in South America where it was reported that oxytocin helps control the peripheral circulation.22
THE ROLE OF OXYTOCIN THROUGHOUT LIFE
Oxytocin at the Time of Birth
It has been reported that the oxytocin inside the fetal brain is responsible for helping a mother go into labor. In rats there is evidence of a signaling system between the mother and the fetus aimed at preparing fetal neurons for delivery. In immature neurons, GABA is the primary excitory neural transmitter. Shortly before delivery, there is a transient reduction in the intracellular chloride concentration and an excitory-to-inhibitory switch of GABA actions occurs. These events are triggered by oxytocin, a maternal hormone that is essential for labor. In vivo administration of an oxytocin receptor antagonist before delivery prevented the switch of the GABA actions in the fetal neurons and aggravated the severity of anoxic episodes experienced by the newborn. Thus, oxytocin inhibits fetal neurons and increases the resistance to insults during delivery23,24
Oxytocin and Stem Cells
Oxytocin induces differentiation of the P19 embryonic stem cells to cardiomyocytes.25-28 Oxytocin is known to stimulate stem cells inside the bone marrow to make more bone tissue.27 Oxytocin also inhibits proliferation of human breast cancer lines.29
Oxytocin Acts as a Paracrine Hormone
As a neuropeptide, oxytocin helps in partition and lactation. Oxytocin plays a pivotal role in memory processing, regulation of body temperature, blood pressure control, brain development, maternal behavior and sexual behavior.1 Oxytocin behaves as a paracrine hormone at the level of the ovary, the testes, the adrenals, the retina, the pineal gland, the thymus, the uterus, the placenta, and the prostate.30- 34 As a paracrine ovarian hormone, there is a rise in the amount of oxytocin around the time of ovulation, and this rise lasts approximately 4 days. There is a second minor increase in oxytocin levels during the luteal phase. Oxytocin is known to be luteolytic. Oxytocin can stimulate motility of the reproductive tract and oxytocin downregulates progesterone production by the corpus luteum.35-39 Oxytocin is produced in the placenta as well as in the decidua of the uterus.40-44 Oxytocinase (also known as cystine aminopeptidase) is also produced in the placenta to deactivate oxytocin during pregnancy and thus keep the uterus from going into premature labor. But as labor begins, the level of oxytocinase decreases, thereby allowing oxytocin to initiate the contractions of labor and delivery.45-47 In males, oxytocin is also produced in the leydig cells of the testes. Oxytocin stimulates tubular activity, and this, in turn, is related to androgen production.48-57 Oxytocin modulates testosterone steroidogenesis and increases activity of 5 alpha-reductase, which converts testosterone to DHT.48, 57, 58
Several different mechanisms operate to destroy oxytocin in the bloodstream. The main mechanism is a peptidase that has the ability to destroy oxytocin. Other agents that work to destroy oxytocin in the bloodstream include an enzyme called cystine aminopeptidase, also known as oxytocinase, found in the placenta; a peptidase called glutothyone hormone transhydrogenase, found in the liver; amiopeptidase, found in the liver, kidney, pituitary, and cerebral cortex; and an enzyme called trypsin-chymotrypsin-like enzyme, found in the liver, kidney, uterus, and cerebral cortex.
Oxytocin and Thyroid Function
Oxytocin is known to stimulate the making of the sodium iodide symporter.59 The symporter is a channel through which the body has the ability to increase the absorption of iodine into the cells. Both oxytocin and prolactin stimulate the sodium iodide symporter system.
Oxytocin as an Adrenal Hormone
When given from an external source oxytocin will decrease cortisol production via inhibition of ACTH production from the hypothalamus.60 The more oxytocin given, the less cortisol is produced by the adrenals.
Oxytocin as a Pancreatic Hormone
Oxytocin stimulates the pancreas to make glucagon and to help control blood sugars.61-65
Oxytocin as a Prostate Hormone
Oxytocin helps in the maintenance of prostatic tone. Oxytocin helps in the contraction of the prostate at the time of orgasm.31,54,57,66
Oxytocin as a Molecular Mimic
Oxytocin has the ability to do what is called molecular mimicry. That is, oxytocin can look like many other hormones inside the body and can mimic some of their functions. For instance, oxytocin can mimic interleukin (IL)-2.67-72 Thymic nursing cells will use oxytocin to process T-cells for their future work. It is of interest that thymic nursing cells are constantly screening all lymphocytes that are processed and become T-cells for reactivity to oxytocin. If a thymic nursing cell finds a T-cell that has the ability to react to oxytocin, the T-cell is immediately destroyed by the thymic nursing cells so that no white blood cells produced by the T-cell system of the thymus has the ability to react against oxytocin. Not only can oxytocin behave like IL-2, it can behave like insulin with one-fifth the activity of the insulin molecule,73 like arginine vasopressin to vasodilate blood vessels inside the brain,74 and like an opioid with the ability to kill pain via the central nervous system.75-78
Oxytocin’s Role in Certain Diseases
Low levels of oxytocin have been found when certain illnesses are present. In Prader-Willi Syndrome there are reduced numbers of oxytocin-producing neurons inside the hypothalamus. Children with autism have been found to have low levels of oxytocin. In actuality, these children are making OT-X (oxytocin extended form). Children with autism do not have the enzyme that is necessary for the breaking up of the oxytocin peptide union, and as a result, very little oxytocin is present inside the blood stream. However, there is plenty of OT-X. The peptide on the oxytocin molecule is on the C-terminal end, where we find the peptides being glycine or glycine-lysine or glycine-lysine and arginine. Once more, these amino-acids have to be disassociated from the oxytocin molecule. The disassociation occurs in the presence of an enzyme that is not being produced in the autistic child, or, if present, is produced in very low levels.79-80 Since oxytocin blood levels are very low in the presence of autism, one would have to wonder if many of the symptoms of autism are not in actuality oxytocin deficiency. A closer look at mounting research studies reveal that low levels of oxytocin are associated with increased risk of certain medical conditions and life events, including:
- Prader Willi syndrome 85-87
- Low estrogen states89
- Low thyroid (T3) levels67
- CMV infection16
- Multiple sclerosis92
- Chronic stress situations94
- Chronic opioid use51
- Parkinson’s disease95
- Anxiety disorders97
- Some types of schizophrenia98
Oxytocin Production: Stimulants and Suppressants
There are several things that serve to increase oxytocin levels in the body. Stimulators of oxytocin production in both males and females include estrogen, histamine, physical touch, acetylcholine, tactile genital stimulation, and intercourse.99-106 The stimulating influence of estrogen explains why women tend to have higher levels of oxytocin than men and why estrogen deprivation in women decreases oxytocin levels. In the book, Harrison’s Principles of Internal Medicine (1998 14th edition, page 2011) the following statement was made: “The manipulation or distention of the female genital tract artificially or during partition is a very strong stimulus for oxytocin production in the brain. The same is true when the breasts are suckled. Touch deprivation, alcohol consumption, chronic pain, and habitual use of narcotics all downregulate oxytocin production.” In premenopausal women, hugging their husbands or partners stimulates the body to produce higher levels of oxytocin.107 Oxytocin is a vasodilator, and hence lowers the blood pressure in women.
Oxytocin and Arginine Vasopressin in Human Emotions and Behaviors
Both oxytocin and arginine vasopressin (AVP) increase the need for social contact and contribute to positive social behavior, increase social bonding, decrease anxiety, increase the desire for single rather than multiple partner selection, increase sexual behavior, improve memory processes (oxytocin primarily improves the memory that is attached to emotion), and upregulate parasympathetic autonomic functions. Oxytocin reduces stress, contributes to relaxation and a sense of well-being, decreases aggression (more so in men than in women), decreases glucocorticoid release, increases sensory processing, increases the desire for touching, and increases the bonding between mates and between parents and children. It is released in a pulsatile manner (this is what increases uterine contractions during birth and body contractions during orgasm). Oxytocin is felt to be a key player in sexual and reproductive behavior since it is involved from the start of the falling-in-love process, to the conception of children, to the sustaining of a lasting and beneficial relationship. It is oxytocin that instills trust, loyalty and devotion – all key ingredients in a happy and fulfilling relationship. Oxytocin induces parenting behavior, promotes affectionate behavior, and in some cases, has been linked to obsessive compulsive disorder.
AVP increases blood pressure, increases territorial and flight or fight behaviors (more so in men than in women), modulates corticoid release, is a component of the stress response, increases reward and limbic processing, and is an oxytocin agonist / partial antagonist.108
Oxytocin as a Biological Probe
Oxytocin can be used as a biological probe in the medical office. Oxytocin can be used to probe the phosphatidylinositol pathway to see if it is intact.109-111 The phosphatidylinositol pathway is necessary to night vision, and it is crucial to the proper functioning of the natural killer (NK) cells of the immune system. This pathway is the major path for the body to respond to oxytocin. The nasal spray form of oxytocin is often used to stimulate women to produce milk when trying to nurse their children. If a woman uses oxytocin nasal spray and has no increase in her milk production, one must consider a breakdown of the phosphatidylinositol pathway. Oxytocin used as a probe can also help determine the source of decreased sex drive in both men and women. The female sex drive is controlled by DHEA, and the male sex drive is controlled primarily by testosterone, which cannot be produced without DHEA.112 Since DHEA is necessary for oxytocin to function properly in the body, oxytocin can be used as a probe for DHEA insufficiency. Observable signs of an oxytocin insufficiency, and hence, of a DHEA insufficiency, include cold extremities (one of the first descriptions given about oxytocin back in 1959 was its ability to control the microcirculation in the peripheral tissues) and a pale skin color.113 However, an injection of oxytocin will provide a better indicator. The oxytocin injection is given intramusclarly using 10 units/cc with 1⁄4 cc lidocaine. Oxytocin has a pH of approximately 4.5, which causes pain when injected alone, so the use of lidocaine helps take the sting out of the injection. Since oxytocin is a vasodilator, within 15 minutes, the hands should warm and the ears should turn red if there is sufficient DHEA to enable proper functioning of the oxytocin. The rest of the body may also turn pink or red in response to the oxytocin if DHEA levels are sufficient. Typically, DHEA blood levels of over 200 mcg/dl are adequate for a clinical response to the oxytocin injection and for normal sex drive (DHEA levels less than 150mcg/dl can result in decreased sex drive). If there is no response to the oxytocin injection, a DHEA insufficiency should be considered, and blood work should be done to confirm this suspicion. If the blood work does indeed reveal a DHEA insufficiency, the patient is typically started on 25 mg/day DHEA if the patient’s age is less than 50 and on 50 mg/day if the patient’s age is 50 or above. Often, 2,000 mg/day of inositol is prescribed along with the DHEA. Both DHEA and inositol promote the development of the phosphatidylinositol pathway. The patient can be rechallenged with the oxytocin/lidocaine injection after 3 months of taking DHEA and inositol. Once there is sufficient DHEA for oxytocin to function properly, sexual desire and performance should be enhanced in both the male and the female.
Oxytocin and Sexual Behavior
In the female brain oxytocin facilitates female sexual maturation through a glia-2-neuron signaling pathway.114 The female brain is marinated in the presence of estrogen, progesterone, and oxytocin, with oxytocin being the number one neural peptide inside the brain. The male brain is marinated in testosterone, mularian inhibitory substance and AVP. Oxytocin rises in response to touch (more in females than in the males), and oxytocin can increase the desire for cuddling. In both men and women, oxytocin levels go up with sexual response.115,116 In men, the surge of oxytocin that occurs with an orgasm will make most of them sleepy and will decrease their interest in sex. In some humans it can impair memory, which is why lovemaking can wipe out the impact of an argument. This also explains why oxytocin has been used in treatment for post traumatic stress disorder (PTSD) over the last 20-30 years.117 In women, oxytocin may cause sexual desire to increase.
Oxytocin and Sexual Performance
Women who are multiorgasmic have much higher levels of plasma oxytocin and have a more subjective intensity of orgasm.118 Oxytocin is commercially available (via a prescription) in the form of injectibles, time-released tablets (10 and 20 units), sublingual tablets (10 to 40 units) and as a nasal spray. If oxytocin is administered to a woman, there will be an increased receptivity to sex, and with appropriate stimulation, she should respond within one hour. Some female patients have reported an increase in the number of multiple orgasms (usually within 3 hours of oxytocin exposure). Oxytocin has been found to be the main hormone responsible for erection in males. Reports from the field show that men who take the sublingual tablets are able to have an erection within 15 minutes. In both sexes oxytocin controls the arousal mechanism. From a clinical standpoint, patients have reported that oxytocin supplementation therapy (10 units IM with 1⁄4 cc lidocaine) produces more intense orgasms for both men and women of all ages. In patients above age 35, DHEA replacement therapy may also be necessary (see above). Other noteworthy facts include the following: oxytocin given intramuscularly to a non- pregnant uterus does not give uterine cramps; oxytocin stimulates the production of vaginal secretions; oxytocin increases penile sensitivity; oxytocin can cause some uterine contractions during orgasm.
Oxytocin and Sexual Dysfunction
In America, orgasmic disorder occurs in 11% of all women and is seen often in patients taking selective serotonin reuptake inhibitors (SSRIs). When male rats were given fluoxetine, researchers documented inhibited sexual performance. The same response has been noted in humans. However, when these same rats were given oxytocin, the ejaculatory response was restored.119 120
Oxytocin and Aging
Levels of estrogen, thyroid hormone, and dopamine, all of which stimulate the synthesis of oxytocin, decrease with age. The number of neurons that make oxytocin does not decrease with aging, but several of the major stimulants to oxytocin production do decline during the aging process.121, 122
Oxytocin has traditionally been given primarily for labor and delivery. In a study of premenopausal women, hugging their partner produced higher levels of oxytocin. Since oxytocin is a vasodilator, it lowered the blood pressure in this group of women. Women who are multiorgasmic have much higher levels of plasma oxytocin and have a more subjective intensity of orgasm. From a clinical standpoint, patients’ feedback indicates that oxytocin hormone replacement therapy can produce more intense orgasms for women of all ages and can, in some women, produce more orgasms. In patients above age 35, DHEA replacement therapy may be necessary. Oxytocin exposure to a non-pregnant woman with a uterus, does not give uterine cramps. Oxytocin stimulates the production of vaginal secretions.123 From the time oxytocin is given until the time the orgasm occurs is about one hour; for women who are multiorgasmic, the time from exposure to oxytocin until the start of this event is about three hours. Oxytocin can make a person desire to cuddle more. In men, oxytocin will make some of them sleepy and have loss of interest in sex. In women exposed to oxytocin, sexual desire goes up. Oxytocin promotes touching, promotes bonding between mates, in parents and children. It is involved in the birthing process and breastfeeding, decreases cognition in some individuals, and may or may not impair memory. Oxytocin is secreted by multiple organs in the body – not just the posterior pituitary. Oxytocin has a synergistic relationship with estrogen. It is pulsatile and can be difficult to measure. Oxytocin and dopamine modulate each other. Oxytocin increases the skin desire to be touched. Oxytocin spikes at the time of an orgasm, increases sexual receptivity, speeds ejaculation, increases penile sensitivity, and can cause some uterine contractions during orgasm and during labor. Oxytocin rises in response to touch in the female, but this response is not frequently seen in the male. Oxytocin promotes touching, induces parenting behavior, and promotes affection behavior. Oxytocin has been used to induce labor, to reduce postpartum bleeding, and to treat schizophrenia.81-84 Since oxytocin blood levels are very low in the presence of autism, one would have to wonder if many of the symptoms of autism are in actuality oxytocin deficiency. In fact, the autistic child might provide us with the definition of an oxytocin deficiency, which to date has not been defined by traditional endocrinology.
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