Premature ovarian failure
Encyclopedia
Premature Ovarian Failure (POF), also known as premature ovarian insufficiency, primary ovarian insufficiency (this is the most accurate term as some women may still conceive), premature menopause
, hypergonadotropic hypogonadism, is the loss of function of the ovaries before age 40. A commonly cited triad for the diagnosis is amenorrhea, hypergonadotropinism, and hypoestrogenism
. If it has a genetic cause, it may be called gonadal dysgenesis
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: 'age not-yet old menstrual water cut-off').
.
POF is not the same as a natural menopause, in that the dysfunction of the ovaries, loss of eggs, or removal of the ovaries at a young age is not a natural physiological occurrence.
Infertility is the 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 or decreased bone density affects almost all women with POF due to an insufficiency of estrogen. There is also an increased risk of heart disease, hypothyroidism
in the form of Hashimoto's thyroiditis
, Addison's disease
, and other auto-immune disorders.
Hormonally, POF 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 shriveled.
The age of onset can be as early as the teenage years, but varies widely. If a girl never begins menstruation, it is called primary ovarian failure. The age of 40 was chosen as the cut-off point for a diagnosis of POF. This age was chosen somewhat arbitrarily, as all women's ovaries decline in function over time, however an age needed to be chosen to distinguish usual menopause from the abnormal state of premature menopause. Premature ovarian failure however often has components to it that distinguish it from normal menopause.
By the age of 40, approximately one percent of women have POF. Women suffering from POF usually experience menopausal symptoms that are more severe than the symptoms found in older menopausal women.
. Some cases of POF are attributed to autoimmune disorders, others to genetic disorders such as Turner syndrome
and Fragile X syndrome
. An Indian study showed a strong correlation between incidence of POF and certain variants in the inhibin alpha gene. In many cases, the cause cannot be determined. Chemotherapy and radiation treatments for cancer can sometimes cause ovarian failure. In natural menopause, the ovaries usually continue to produce low levels of hormones, but in chemotherapy or radiation-induced POF, the ovaries will often cease all functioning and hormone levels will be similar to those of a woman whose ovaries have been removed. Women who have had their tubes tied, or who have had hysterectomies, tend to go through menopause several years earlier than average, likely due to decreased blood flow to the ovaries. Family history and ovarian or other pelvic surgery earlier in life are also implicated as risk factors for POF.
There are two basic kinds of premature ovarian failure. Case 1) where there are few to no remaining follicles and case 2) where there are an abundant number of follicles. In the first situation the causes include genetic disorders, autoimmune damage, chemotherapy, radiation to the pelvic region, surgery, endometriosis and infection. In most cases the cause is unknown. In the second case one frequent cause is autoimmune ovarian disease which damages maturing follicles, but leaves the primordial follicles intact. Also, in some women FSH may bind to the FSH receptor site, but be inactive. By lowering the endogenous FSH levels with ethinyl estradiol (EE) or with a GnRH-a the receptor sites are freed and treatment with exogenous recombinant FSH activates the receptors and normal follicle growth and ovulation can occur. (Since the serum anti-müllerin hormone
(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.)
The POF Fact Sheet lists potential causes of POF in various languages:
http://www.pofsupport.org/information_center.asp
Genetic associations include:
(FSH) measurement alone can be used to diagnose the disease. Two FSH measurements with one-month interval have been a common practice. The anterior pituitary secretes FSH and LH at high levels due to the dysfunction of the ovaries and consequent low estrogen levels. Typical FSH in POF patients is over 40 mlU/ml (post-menopausal range).
for a summary of recent randomized clinical trials and treatment methods.)
Currently New York fertility researchers are investigating the use of a mild male hormone called dehydroepiandrosterone (DHEA) in women with POF to increase spontaneous pregnancy rates. Published results from studies conducted on DHEA have indicated that DHEA may increase spontaneously conceived pregnancies, decrease spontaneous miscarriage rates and improve IVF success rates in women with POF.
Additionally, over the last five years a Greek research team has successfully implemented the use of dehydroepiandrosterone (DHEA) for the fertility treatment of women suffering with POF.The majority of the patients were referred for donor eggs or surrogacy, however after a few months of DHEA administration they succeeded in getting pregnant through IVF, IUI, IUTPI or natural conception. Until now a great number of babies have been born after treatment with DHEA.
Ovarian tissue cryopreservation
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.
activities, resulting in osteopenia
as well as osteoporosis
. Furthermore, most of the patients develop symptoms of estrogen
deficiency, including vasomotor flushes and vaginal dryness, both of which respond to estrogen
therapy effectively. There are several contraindications of estrogen
supplement, including smokers over 35 years of age, uncontrolled hypertension
, uncontrolled diabetes mellitus
, or history of thromboemboli events. If the patient has strong family history of thromboemboli events, care must be taken to proceed with the hormonal replacement therapy. As the minimum, testing for Factor V Leiden
, Protein C
, and Protein S
should be performed to ensure the low risk of developing thromboemboli events while on the estrogen replacement.
The transdermal estradiol patch (typically 100 mcg) is commonly recommended because of several advantages. It provides the replacement by steady infusion rather than by bolus when taking daily pills. It also avoids the first-pass effect in the liver.
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
, hypergonadotropic hypogonadism, is the loss of function of the ovaries before age 40. A commonly cited triad for the diagnosis is amenorrhea, hypergonadotropinism, and hypoestrogenism
Hypoestrogenism
Hypoestrogenism refers to a lower than normal level of estrogen, the primary sex hormone for women. In general, lower levels of estrogen may cause differences in the breasts, genitals, urinary tract and skin....
. If it has a genetic cause, it may be called gonadal dysgenesis
Gonadal dysgenesis
Gonadal dysgenesis is a term used to describe multiple reproductive system development disorders. They are conditions of genetic origin. It is characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo....
History
Fuller Albright et al. in 1942 first reported a syndrome in young women characterized by menopausal levels of follicle stimulating hormone (FSH), low estrogen levels and amenorrhea. They named the condition "primary ovarian insufficiency" to distinguish the condition from secondary ovarian insufficiency, which is the failure of the pituitary to secrete FSH. Chapter 28 of the early Qing dynastyQing Dynasty
The Qing Dynasty was the last dynasty of China, ruling from 1644 to 1912 with a brief, abortive restoration in 1917. It was preceded by the Ming Dynasty and followed by the Republic of China....
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: 'age not-yet old menstrual water cut-off').
Presentation
On average, the ovaries supply a woman with eggs until age 51, the average age of natural menopauseMenopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
.
POF is not the same as a natural menopause, in that the dysfunction of the ovaries, loss of eggs, or removal of the ovaries at a young age is not a natural physiological occurrence.
Infertility is the 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 or decreased bone density affects almost all women with POF due to an insufficiency of estrogen. There is also an increased risk of heart disease, hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
in the form of Hashimoto's thyroiditis
Hashimoto's thyroiditis
Hashimoto's thyroiditis or chronic lymphocytic thyroiditis is an autoimmune disease in which the thyroid gland is gradually destroyed by a variety of cell- and antibody-mediated immune processes. It was the first disease to be recognized as an autoimmune disease...
, Addison's disease
Addison's disease
Addison’s disease is a rare, chronic endocrine disorder in which the adrenal glands do not produce sufficient steroid hormones...
, and other auto-immune disorders.
Hormonally, POF is defined by abnormally low levels of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
and high levels of FSH
FSH
FSH may refer to:* Follicle-stimulating hormone* Fox Sports Houston, a regional Fox Sports Net affiliate station for the Houston, Texas area* Facioscapulohumeral muscular dystrophy* International Civil Aviation Organisation code for Flash Airlines...
, which demonstrate that the ovaries are no longer responding to circulating FSH by producing estrogen and developing fertile eggs. The ovaries will likely appear shriveled.
The age of onset can be as early as the teenage years, but varies widely. If a girl never begins menstruation, it is called primary ovarian failure. The age of 40 was chosen as the cut-off point for a diagnosis of POF. This age was chosen somewhat arbitrarily, as all women's ovaries decline in function over time, however an age needed to be chosen to distinguish usual menopause from the abnormal state of premature menopause. Premature ovarian failure however often has components to it that distinguish it from normal menopause.
By the age of 40, approximately one percent of women have POF. Women suffering from POF usually experience menopausal symptoms that are more severe than the symptoms found in older menopausal women.
Causes
The cause of POF is usually idiopathicIdiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
. Some cases of POF are attributed to autoimmune disorders, others to genetic disorders such as Turner syndrome
Turner syndrome
Turner syndrome or Ullrich-Turner syndrome encompasses several conditions in human females, of which monosomy X is most common. It is a chromosomal abnormality in which all or part of one of the sex chromosomes is absent...
and Fragile X syndrome
Fragile X syndrome
Fragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability...
. An Indian study showed a strong correlation between incidence of POF and certain variants in the inhibin alpha gene. In many cases, the cause cannot be determined. Chemotherapy and radiation treatments for cancer can sometimes cause ovarian failure. In natural menopause, the ovaries usually continue to produce low levels of hormones, but in chemotherapy or radiation-induced POF, the ovaries will often cease all functioning and hormone levels will be similar to those of a woman whose ovaries have been removed. Women who have had their tubes tied, or who have had hysterectomies, tend to go through menopause several years earlier than average, likely due to decreased blood flow to the ovaries. Family history and ovarian or other pelvic surgery earlier in life are also implicated as risk factors for POF.
There are two basic kinds of premature ovarian failure. Case 1) where there are few to no remaining follicles and case 2) where there are an abundant number of follicles. In the first situation the causes include genetic disorders, autoimmune damage, chemotherapy, radiation to the pelvic region, surgery, endometriosis and infection. In most cases the cause is unknown. In the second case one frequent cause is autoimmune ovarian disease which damages maturing follicles, but leaves the primordial follicles intact. Also, in some women FSH may bind to the FSH receptor site, but be inactive. By lowering the endogenous FSH levels with ethinyl estradiol (EE) or with a GnRH-a the receptor sites are freed and treatment with exogenous recombinant FSH activates the receptors and normal follicle growth and ovulation can occur. (Since the serum anti-müllerin hormone
Anti-müllerian hormone
Anti-Müllerian hormone also known as AMH is a protein that, in humans, is encoded by the AMH gene. It inhibits the development of the Müllerian ducts in the male embryo. It has also been called Müllerian inhibiting factor , Müllerian-inhibiting hormone , and Müllerian-inhibiting substance...
(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.)
The POF Fact Sheet lists potential causes of POF in various languages:
http://www.pofsupport.org/information_center.asp
- Genetic disorders
- Autoimmune diseases
- Tuberculosis of the genital tract
- Smoking
- Radiation and/or chemotherapy
- Ovarian failure following hysterectomy
- Prolonged gnrh therapy
- Enzyme defects
- Resistant ovary
- Induction of multiple ovulation in infertility
Genetic associations include:
| Type | OMIM | Gene | Locus |
|---|---|---|---|
| POF1 | FMR1 FMR1 FMR1 is a human gene that codes for a protein called fragile X mental retardation protein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function... |
Xq26-q28 | |
| POF2A | DIAPH2 DIAPH2 Protein diaphanous homolog 2 is a protein that in humans is encoded by the DIAPH2 gene.-Further reading:... |
Xq13.3-q21.1 | |
| POF2B | POF1B POF1B Protein POF1B is a protein that in humans is encoded by the POF1B gene.-Further reading:... |
Xq13.3-q21.1 | |
| POF3 | FOXL2 | 3q23 | |
| POF4 | BMP15 | Xp11.2 | |
| POF5 | NOBOX NOBOX Homeobox protein NOBOX, also known as newborn ovary homeobox protein, is a protein that in humans is encoded by the NOBOX gene.- Function :NOBOX is a homeobox gene that is preferentially expressed in oocytes... |
7q35 | |
| POF6 | FIGLA FIGLA Folliculogenesis-specific basic helix-loop-helix, also known as factor in the germline alpha or transcription factor FIGa, is a protein that in humans is encoded by the FIGLA gene.- Function :... |
2p12 | |
| POF7 | NR5A1 | 9q33 |
Laboratory
Serum follicle-stimulating hormoneFollicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
(FSH) measurement alone can be used to diagnose the disease. Two FSH measurements with one-month interval have been a common practice. The anterior pituitary secretes FSH and LH at high levels due to the dysfunction of the ovaries and consequent low estrogen levels. Typical FSH in POF patients is over 40 mlU/ml (post-menopausal range).
Fertility
Between 5 and 10 percent of women with POF may spontaneously become pregnant. Currently no fertility treatment has officially been found to effectively increase fertility in women with POF, and the use of donor eggs with In-Vitro Fertilization (IVF) and adoption have become more popular as a means of becoming parents for women with POF. Some women with POF choose to live child-free. (See Impaired Ovarian ReservePoor ovarian reserve
Poor ovarian reserve is a condition of low fertility characterized by 1): low numbers of remaining oocytes in the ovaries or 2) possibly impaired preantral oocyte development or recruitment...
for a summary of recent randomized clinical trials and treatment methods.)
Currently New York fertility researchers are investigating the use of a mild male hormone called dehydroepiandrosterone (DHEA) in women with POF to increase spontaneous pregnancy rates. Published results from studies conducted on DHEA have indicated that DHEA may increase spontaneously conceived pregnancies, decrease spontaneous miscarriage rates and improve IVF success rates in women with POF.
Additionally, over the last five years a Greek research team has successfully implemented the use of dehydroepiandrosterone (DHEA) for the fertility treatment of women suffering with POF.The majority of the patients were referred for donor eggs or surrogacy, however after a few months of DHEA administration they succeeded in getting pregnant through IVF, IUI, IUTPI or natural conception. Until now a great number of babies have been born after treatment with DHEA.
Ovarian tissue cryopreservation
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 is threatened by cancer therapy, for example in...
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.
Hormonal replacement
It is important to initiate the hormonal replacement therapy after the diagnosis of POF, as untreated patients are at a great risk of bone loss due to increased osteoclastOsteoclast
An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...
activities, resulting in osteopenia
Osteopenia
Osteopenia is a condition where bone mineral density is lower than normal. It is considered by many doctors to be a precursor to osteoporosis. However, not every person diagnosed with osteopenia will develop osteoporosis...
as well as osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
. Furthermore, most of the patients develop symptoms of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
deficiency, including vasomotor flushes and vaginal dryness, both of which respond to estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
therapy effectively. There are several contraindications of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
supplement, including smokers over 35 years of age, uncontrolled hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, uncontrolled diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, or history of thromboemboli events. If the patient has strong family history of thromboemboli events, care must be taken to proceed with the hormonal replacement therapy. As the minimum, testing for Factor V Leiden
Factor V Leiden
Factor V Leiden is the name given to a variant of human factor V that causes a hypercoagulability disorder. In this disorder the Leiden variant of factor V cannot be inactivated by activated protein C. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst Eurasians...
, Protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...
, and Protein S
Protein S
Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the endothelium. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b. In humans, protein S is encoded by the PROS1 gene...
should be performed to ensure the low risk of developing thromboemboli events while on the estrogen replacement.
The transdermal estradiol patch (typically 100 mcg) is commonly recommended because of several advantages. It provides the replacement by steady infusion rather than by bolus when taking daily pills. It also avoids the first-pass effect in the liver.
In popular culture
In the fourth season of the British television show Skins, the character Katie Fitch is diagnosed with this after going in for a pregnancy test (since she missed several periods). This greatly upsets her because of her wish to have a family one day, and informs her character development.External links
- International Premature Ovarian Failure Association
- POF Fact Sheets, FAQ
- POF Awareness Campaign for patients and health care providers
- National Institutes of Health publication No. 03-5159, Do I have Premature Ovarian Failure?
- National Institutes of Health's Premature Ovarian Failure website