Primary
ovarian
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body ...
insufficiency (POI) (also called premature ovarian insufficiency, premature menopause, and premature ovarian failure) is the partial or total loss of
reproductive and
hormonal
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required f ...
function of the ovaries before age 40 because of
folliclular (
egg
An egg is an organic vessel grown by an animal to carry a possibly fertilized egg cell (a zygote) and to incubate from it an embryo within the egg until the embryo has become an animal fetus that can survive on its own, at which point the a ...
producing area) dysfunction or early loss of eggs.
[ POI can be seen as part of a continuum of changes leading to ]menopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often ...
[ that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function.] POI affects approximately 1 in 10,000 women under age 20, 1 in 1,000 women under age 30, and 1 in 100 of those under age 40. A medical triad
A medical triad is a group of three signs or symptoms, the result of injury to three organs, which characterise a specific medical condition. The appearance of all three signs conjoined together in another patient, points to that the patient has t ...
for the diagnosis is amenorrhea
Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses ...
, hypergonadotropism, and hypoestrogenism
Hypoestrogenism, or estrogen deficiency, refers to a lower than normal level of estrogen. It is an umbrella term used to describe estrogen deficiency in various conditions. Estrogen deficiency is also associated with an increased risk of cardiova ...
.[
Physical and emotional symptoms include ]hot flashes
Hot flashes (also known as hot flushes) are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and ...
, night sweats
Night sweats, also referred to as nocturnal hyperhidrosis (Hyperhidrosis - a medical term for excessive sweating + nocturnal - night), is the repeated occurrence of excessive sweating during sleep
Sleep is a sedentary state of mind and bo ...
, dry skin
Xeroderma, xerosis or xerosis cutis, or simply dry skin, is a skin condition characterized by excessively dry skin.
The medical term ''xeroderma'', meaning "dry skin", derives from modern Latin, ''xero-'' 'dry' + Greek ''derma'' 'skin'.
In most ...
, vaginal dryness
Vaginal lubrication is a naturally produced fluid that lubricates a
vagina. Vaginal lubrication is always present, but production increases significantly near ovulation and during sexual arousal in anticipation of sexual intercourse. Vaginal ...
, irregular or absent menstruation, anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
, depression, mental fog
Clouding of consciousness (also known as brain fog or mental fog) occurs when a person is slightly less wakeful or aware than normal. They are not as aware of time or their surroundings and find it difficult to pay attention. People describe th ...
, irritability, nervousness, decreased libido
Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act u ...
, and increased autoimmune disruption.[ The sense of shock and distress on being informed of the diagnosis can be overwhelming.][ The general treatment is for symptoms, bone protection, and ]mental health
Mental health encompasses emotional, psychological, and social well-being, influencing cognition, perception, and behavior. It likewise determines how an individual handles stress, interpersonal relationships, and decision-making. Mental hea ...
. Although 5 to 10% of women with POI may ovulate
Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized ...
sporadically and become pregnant without treatment, others may use assisted reproductive technology including in vitro fertilization
In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...
and egg donation
Egg donation is the process by which a woman donates eggs to enable another woman to conceive as part of an assisted reproduction treatment or for biomedical research. For assisted reproduction purposes, egg donation typically involves in vitro ...
or decide to adopt or remain childless.
The causes of POI are heterogeneous and are unknown in 90% of cases.[ It can be associated with genetic causes, autoimmune disease, ]enzyme deficiency
Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances ( substra ...
, infection, environmental factors, radiation, or surgery in 10%. Two to 5% of women with POI and a premutation in FMR1
''FMR1'' (Fragile X Messenger Ribonucleoprotein 1) is a human gene that codes for a protein called ''fragile X messenger ribonucleoprotein'', or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development ...
, a genetic abnormality, are at risk of having a child with fragile X syndrome, the most common cause of inherited intellectual disability
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signif ...
.[
The diagnosis is based on ages less than 40, amenorrhea, and elevated serum follicle-stimulating hormone (FSH) levels.] Typical serum FSH levels in POI patients is in the post-menopausal range.[ Treatment will vary depending on the symptoms. It can include hormone replacement therapy, fertility management, and psychosocial support, as well as annual screenings of ]thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
and adrenal
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...
function.
Signs and symptoms
The signs and symptoms of POI can be seen as part of a continuum of changes leading to menopause.[ POI contrasts with age-appropriate menopause in the age of onset, degree of symptoms and sporadic return to normal ovarian function.][ As some women retain partial ovarian function, symptoms may not be as severe as regular menopause.][ In others, particularly with coexistent depression, symptoms such as decreased ]quality of life
Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
can be severe.
Hormonally, POI is defined by abnormally low levels of estrogen and high levels of FSH, which demonstrate that the ovaries are no longer responding to circulating FSH by producing estrogen and developing fertile eggs. The ovaries will likely appear smaller than normal. The age of onset can be as early as 11 years. POI can be seen as part of a continuum of changes leading to menopause[ that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function.][ A contrasting problem can be when a girl never begins menstruation due to a genetic condition causing primary amenorrhea.][
]
Causes
The cause of POI is idiopathic
An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. From Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approximately "a disease of its own kin ...
in 90% of cases.[ Some cases of POI are attributed to autoimmune disorders such as ]autoimmune oophoritis
Autoimmune oophoritis is a rare autoimmune disease where the body's own immune system attacks the ovaries. This causes the ovaries to have inflammation, atrophy, and fibrosis. Such changes in the ovaries can cause them to not function properly. Th ...
, Hashimoto thyroiditis
Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto's disease, is an autoimmune disease in which the thyroid gland is gradually destroyed. Early on, symptoms may not be noticed. Over time, the thyroid may enla ...
, Addison disease
Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adre ...
, type I diabetes mellitus
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...
, pernicious anemia
Pernicious anemia is a type of vitamin B12 deficiency anemia, a disease in which not enough red blood cells are produced due to the malabsorption of vitamin B12. Malabsorption in pernicious anemia results from the lack or loss of intrinsic fa ...
, genetic disorders such as Turner syndrome
Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hair ...
and Fragile X syndrome, metabolic defects, and enzyme defects.[ One study showed a strong correlation between incidence of POI and certain variants in the ]inhibin alpha
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual c ...
gene. Chemotherapy and radiation treatments for cancer can sometimes cause POI. The effect of chemotherapy or radiation is variable and in a mouse model, with results consistent with observations in humans, cyclophosphamide can result in an 87% reduction in primordial follicles 72 hours after administration.[ Women who have had a hysterectomy tend to go through menopause early and have a nearly twofold increased risk of POI.][ Almost any pelvic surgery has the potential to damage the ovary by affecting its blood supply or causing inflammation in the area resulting in POI.][
]
Galactosemia
Women who have inherited classic galactosemia
Galactose-1-phosphate uridylyltransferase deficiency (classic galactosemia) is the most common type of galactosemia, an inborn error of galactose metabolism, caused by a deficiency of the enzyme galactose-1-phosphate uridylyltransferase. It is a ...
( galactose intolerance) may develop primary ovarian insufficiency.
Mechanism
The pathogenic mechanisms of POI are highly heterogeneous and can be divided into four major categories: follicular migration defect early in embryogenesis; an early decrease in the primordial follicles; increased follicular death; and altered maturation or recruitment of primordial follicles.[ These result in a decrease of the ovaries' general supply of eggs that normally lasts until an average age of 51 for age of age-appropriate ]menopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often ...
.
Genetic causes such as Turner syndrome have initial ovarian development but then ovaries degenerate rapidly during prenatal life, often leading to gonadal dysgenesis with streak ovaries. In those cases where POI is associated with adrenal autoimmunity, histological examination almost always confirms the presence of an autoimmune oophoritis in which follicles are infiltrated by lymphocytes, plasma cells, and macrophages that attack mainly steroid-producing cells and eventually result in follicular depletion.[
In some women FSH may bind to the FSH receptor site, but be inactive. By lowering the endogenous FSH levels with ]ethinylestradiol
Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disord ...
(EE) or with a GnRH-a the receptor sites are free and treatment with exogenous recombinant FSH activates the receptors and normal follicle growth and ovulation can occur. (Since the serum Anti-Müllerian hormone
Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differen ...
(AMH) level is correlated with the number of remaining primordial follicles some researchers believe the above two phenotypes can be distinguished by measuring serum AMH levels.
Genetic associations include genetic disorders,[ autoimmune diseases,][ enzyme defects,][ and resistant ovaries.][
Mutations in FOXL2 cause Blepharophimosis Ptosis Epicanthus inversus Syndrome (BPES). Premature ovarian failure is part of the BPES Type I variant of the syndrome but not of the BPES Type II variant.
]
DNA repair deficiency
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
protein plays an essential role in the repair of DNA double-strand breaks by homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
. Women with a germline BRCA1 mutation tend to have premature menopause as evidenced by the final menorrhea appearing at a younger age. BRCA1 mutations are associated with occult POI. Impairment of the repair of DNA double-strand breaks due to a BRCA1 defect leads to premature ovarian aging in both mice and humans.
In addition to BRCA1, the MCM8
DNA replication licensing factor MCM8 is a protein that in humans is encoded by the ''MCM8'' gene.
The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of ...
-MCM9 protein complex also plays a crucial role in the recombinational repair of DNA double-strand breaks. In humans, an MCM8 mutation can give rise to premature ovarian failure, as well as chromosomal instability. MCM9, as well as MCM8, mutations are also associated with ovarian failure and chromosomal instability. The MCM8-MCM9 complex is likely required for the homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
al repair of DNA double-strand breaks that are present during the pachytene stage of meiosis
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately r ...
I. In women homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
for MCM8 or MCM9 mutations, failure to repair breaks apparently leads to oocyte
An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The femal ...
death and small or absent ovaries
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
.
Diagnosis
The diagnosis is based on age less than forty, amenorrhea for four months or more, and two elevated serum follicle-stimulating hormone (FSH) measurements at one-month intervals. The anterior pituitary secretes FSH and LH at high levels to try to increase the low estrogen levels that are due to the dysfunction of the ovaries. Typical FSH in POI patients is over 40 mlU/ml (post-menopausal range).[
]
Treatment
Fertility
Between 5 and 10 percent of women with POI may become pregnant with no treatment.[ As of 2016 no fertility treatment has been found to effectively increase fertility in women with POI, and the use of donor eggs with ]in-vitro fertilization
In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) ...
(IVF) and adoption are a means of achieving parenthood for women with POI.[ Some women with POI choose to live child-free.][
Researchers have investigated the use of a hormone called ]dehydroepiandrosterone
Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It fun ...
(DHEA) in women with POI to increase spontaneous pregnancy rates. Results from studies on DHEA in 2010 indicated that DHEA may increase spontaneously conceived pregnancies, decrease spontaneous miscarriage rates and improve IVF success rates in women with POI. This includes women referred for donor eggs or surrogacy in 2009. In 2018, there was no significant improvement in ovarian function by 12-month on DHEA supplementation in women with POI.[ Given the inconclusiveness of potential benefits and risks of testosterone and DHEA supplementation, longer-term, randomized studies are warranted for women and girls with POI.]
Ovarian tissue cryopreservation Ovarian tissue cryopreservation is cryopreservation of tissue of the ovary of a female.
Indications
Cryopreservation of ovarian tissue is of interest to women who want fertility preservation beyond the natural limit, or whose reproductive potential ...
can be performed on prepubertal girls at risk for premature ovarian failure, and this procedure is as feasible and safe as comparable operative procedures in children.
In 2013, Kawamura in Japan and his collaborators at Stanford University published treatment of infertility of POI patients by fragmenting ovaries followed by in vitro treatment of ovarian fragments with phosphatidylinositol-3 kinase activators to enhance the AKT pathway followed by autografting. They successfully promoted follicle growth, retrieved mature oocytes, and performed in vitro fertilization. Following embryo transfer, a healthy baby was delivered. A 2020 review covered variations including phosphatidylinositol-3 kinase activators to enhance the AKT pathway, fragmentation of ovarian cortex, combining those two into in-vitro activation (IVA), and drug-free IVA. Two laparoscopies are needed in conventional IVA and one with drug-free IVA.[
]
Hormonal replacement
Women with POI can develop symptoms of estrogen deficiency, including vasomotor flushes and vaginal dryness that respond to physiologic replacement of hormones. Most authorities recommend that this hormone replacement continue until age 50 years, the normal age of menopause. The leading hormone replacement regimen recommended involves the administration of estradiol daily by either skin patch or vaginal ring. This approach reduces the risk of pulmonary embolism
Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream ( embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathin ...
and deep venous thrombosis by avoiding the first pass effect on the liver that is induced by oral estrogen therapy. The transdermal estradiol patch also provides the replacement by steady infusion rather than by bolus when taking daily pills.[
Concerns of estrogen supplement are addressed in The US Medical Eligibility Criteria for Contraceptive Use, 2010 provides guidance for safety of contraceptive methods and include guidance for conditions associated with increased risk of thrombosis such as postpartum, history of thrombosis, thrombogenic mutations, systemic lupus erythematosus, ]diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
, and hypertension. There is also an increased risk with valvular heart disease and cardiomyopathy.
To avoid the development of endometrial cancer young women taking estradiol replacement need also to take a progestin in a regular cyclic fashion. The most evidence supports the use of medroxyprogesterone acetate per day for days one through 12 of each calendar month. This will induce regular and predictable menstrual cycles. It is important that women taking this regimen keep a menstrual calendar. If the next expected menses is late it is important to get a pregnancy test. It this is positive, the woman should stop taking the hormone replacement. Approximately 5 to 10% of women with confirmed POI conceive a pregnancy after the diagnosis without medical intervention.
Prognosis
Infertility can be a result of this condition and is the most discussed problem resulting from it, but there are additional health implications of the problem, and studies are ongoing. For example, osteoporosis (decreased bone density) affects almost all women with POI due to an insufficiency of estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
. There is also an increased risk of heart disease,[ hypothyroidism such as ]Hashimoto's thyroiditis
Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto's disease, is an autoimmune disease in which the thyroid gland is gradually destroyed. Early on, symptoms may not be noticed. Over time, the thyroid may enlarg ...
, Addison's disease
Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adre ...
, and other autoimmune disorders.
Emotional health
The most common words women use to describe how they felt in the two hours after being given the diagnosis of POI are "devastated", "shocked," and "confused."[ The diagnosis is more than infertility and affects a woman's physical and emotional well-being.] Patients face the acute shock of the diagnosis, associated stigma of infertility, grief from the death of dreams, anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
and depression from the disruption of life plans, confusion around the cause, shame, insecurity and lowered self-esteem, anger in reflection of being letdown by the medical system, symptoms of estrogen deficiency, worry over the associated potential medical sequelae such as reduced bone density and cardiovascular risk, and the uncertain future that all of these factors create.[ Women diagnosed with POI in their 20s have disproportionately reported experiencing dismissiveness, bias, and "not being taken seriously" by healthcare professionals.]
There is a need for an evidence-based
Evidence-based practice (EBP) is the idea that occupational practices ought to be based on scientific evidence. While seemingly obviously desirable, the proposal has been controversial, with some arguing that results may not specialize to indiv ...
integrative medicine
Alternative medicine is any practice that aims to achieve the healing effects of medicine despite lacking biological plausibility, testability, repeatability, or evidence from clinical trials. Complementary medicine (CM), complementary and alte ...
program to assist women with POI. Presently such a program does not exist in the community, but a community of practice has formed to address this deficiency. Women with POI perceive lower social support than control women, so building a trusted community of practice for them would be expected to improve their well-being. Also, when having that social support, it often helps with reducing stress and having better coping skills. It is important to connect women with POI to an appropriate collaborative care team because the condition has been clearly associated with suicide related to the stigma of infertility. Suicide rates are known to be increased in women who experience infertility.
Epidemiology
The prevalence increases with age and is approximately 1 in 10,000 women under age 20, 1 in 1,000 women under age 30, and one percent by age of 40.
History
Fuller Albright
Fuller Albright (January 12, 1900 – December 8, 1969) was an American endocrinologist who made numerous contributions to his field, especially to the area of calcium metabolism. Albright made great strides and contributions to the understanding ...
et al. in 1942 reported a syndrome with amenorrhea, estrogen deficiency, menopausal FSH levels, and short stature. They used the term "primary ovarian insufficiency" to distinguished POI from ovarian insufficiency secondary to a primary failure of pituitary
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypoph ...
FSH and other hormonal secretion. POI has been described as a more accurate and less stigmatizing term than premature ovarian failure or premature menopause.[
Chapter 28 of the early ]Qing dynasty
The Qing dynasty ( ), officially the Great Qing,, was a Manchu-led imperial dynasty of China and the last orthodox dynasty in Chinese history. It emerged from the Later Jin dynasty founded by the Jianzhou Jurchens, a Tungusic-spea ...
work ''Fù Qīngzhǔ Nǚkē'' (《傅青主女科》''Fù Qīngzhǔ's Gynecology'') describes the cause and appropriate treatment for premature menopause. 年未老经水断 (niánwèilǎo jīngshuǐduàn) glosses as 'not yet old, menstrual water cut-off.'
References
External links
Primary Ovarian Insufficiency (POI): Overview
National Institutes of Health
{{DEFAULTSORT:Premature Ovarian Failure
Menopause
Fertility
Gynaecologic disorders
Menstrual cycle
Endocrine gonad disorders
Human female endocrine system
Medical triads