Anovulation
Encyclopedia
An anovulatory cycle is a menstrual cycle
Menstrual cycle
The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle....

 during which the ovaries do not release an oocyte
Oocyte
An oocyte, ovocyte, or rarely ocyte, 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 the ovary during female gametogenesis. The female germ cells produce a primordial germ cell which undergoes a mitotic...

. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...

.

In addition to the alteration of menstrual periods and infertility, chronic anovulation can cause or exacerbate other long term problems, such as hyperandrogenism
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...

 or osteopenia
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...

. It plays a central role in the multiple imbalances and dysfunctions of polycystic ovary syndrome
Polycystic ovary syndrome
Polycystic ovary syndrome is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can to a large degree be classified as a genetic disease....

.

During the first two years after menarche 50% of the menstrual cycles could be anovulatories.

It is in fact possible to restore ovulation using appropriate medication, and ovulation is successfully restored in approximately 90% of cases. The first step is the diagnosis of anovulation. The identification of anovulation is not easy; contrary to what is commonly believed, women undergoing anovulation still have (more or less) regular periods. In general, patients only notice that there is a problem once they have started trying to conceive.

Temperature charting is a useful way of providing early clues about anovulation, and can help gynaecologists in their diagnosis.

Hormonal or chemical imbalance

This is the most common cause of anovulation and is thought to account for about 70% of all cases.
  1. About half the women with hormonal imbalances do not produce enough follicles to ensure the development of an ovule
    Ovule
    Ovule means "small egg". In seed plants, the ovule is the structure that gives rise to and contains the female reproductive cells. It consists of three parts: The integument forming its outer layer, the nucellus , and the megaspore-derived female gametophyte in its center...

    . This could be caused by poor hormonal secretions from the pituitary gland
    Pituitary gland
    In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...

     or the hypothalamus
    Hypothalamus
    The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

    .
  2. The pituitary gland
    Pituitary gland
    In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...

     controls most other hormonal glands in the human body. Therefore, any pituitary malfunctioning affects other glands under its influence, which includes ovaries. This occurs in around 10% of the cases. Mammary glands are also controlled by the pituitary gland, which can thus also affect lactation
    Lactation
    Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...

    .
  3. The hypothalamus
    Hypothalamus
    The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

     controls the pituitary gland
    Pituitary gland
    In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...

    . In 10% of the cases, alterations in the chemical signals from the hypothalamus
    Hypothalamus
    The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

     can easily seriously affect the ovaries.
  4. There are other hormonal anomalies with no direct link to the ones mentioned above that can affect ovulation
    Ovulation
    Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...

    . For instance, women with hyper or hypo-thyrodism sometimes have ovulation
    Ovulation
    Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...

     problems. Thyroid
    Thyroid
    The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...

     dysfunction can halt ovulation by upsetting the balance of the body’s natural reproductive hormones. Polycystic ovary syndrome
    Polycystic ovary syndrome
    Polycystic ovary syndrome is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can to a large degree be classified as a genetic disease....

     (also known as Stein-Leventhal syndrome) and hyperprolactinemia can also cause anovulatory cycles through hormonal imbalances.

Functional problem

This accounts for around 10-15% of all cases of anovulation.
  1. The ovaries can stop working in about 5% of cases. This may be because the ovaries do not contain eggs. However, a complete blockage of the ovaries is rarely a cause of infertility
    Infertility
    Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...

    . Blocked ovaries can start functioning again without a clear medical explanation.
  2. A significant emotional shock can temporarily affect the functioning of the brain and can lead to dysfunction of the hypothalamus
    Hypothalamus
    The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

    . However, this is not as common as people might think.
  3. In some cases, the egg may have matured properly, but the follicle
    Ovarian follicle
    Ovarian follicles are the basic units of female reproductive biology, each of which is composed of roughly spherical aggregations of cells found in the ovary. They contain a single oocyte . These structures are periodically initiated to grow and develop, culminating in ovulation of usually a single...

     may have failed to burst (or the follicle may have burst without releasing the egg). This is called luteinised unruptured follicle syndrome (LUFS). Physical damage to the ovaries, or ovaries with multiple cysts, may affect their ability to function. This is called ovarian dystrophy
    Dystrophy
    Dystrophy is any condition of abnormal development, often denoting the degeneration of muscles.-Types:* Muscular dystrophy* Duchenne muscular dystrophy* Becker's muscular dystrophy* Reflex neurovascular dystrophy* Retinal dystrophy* Conal dystrophy...

    . Patients who are suffering from Stein-Leventhal syndrome (also referred to as polycystic ovary syndrome, or PCOS) can also suffer from anovulation. Up to 90% of cases of anovulation are caused by PCOS; this syndrome is usually hereditary.
  4. Weight loss or anorexia
    Anorexia nervosa
    Anorexia nervosa is an eating disorder characterized by refusal to maintain a healthy body weight and an obsessive fear of gaining weight. Although commonly called "anorexia", that term on its own denotes any symptomatic loss of appetite and is not strictly accurate...

     can also cause hormonal imbalance, leading to irregular ovulation (dysovulation). It is possible that this mechanism evolved to protect the mother’s health. A pregnancy where the mother is weak could pose a risk to the baby’s and mother’s health. On the other hand, excess weight can also create ovarian dysfunctions. Dr Barbieri of Harvard Medical School has indicated that cases of anovulation are quite frequent in women with a BMI (body mass index
    Body mass index
    The body mass index , or Quetelet index, is a heuristic proxy for human body fat based on an individual's weight and height. BMI does not actually measure the percentage of body fat. It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing...

    ) over 27 kg/m2. Unfortunately, not only does excess weight have a negative impact on ovulation
    Ovulation
    Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...

     itself, but also on treatment efficacy and outcomes of ART (assisted reproductive technique).

Signs and symptoms

Anovulation is usually associated with specific symptoms. However, it is important to note that they are not necessarily all displayed simultaneously.
  1. Amenorrhea (absence of menstruation
    Menstruation
    Menstruation is the shedding of the uterine lining . It occurs on a regular basis in sexually reproductive-age females of certain mammal species. This article focuses on human menstruation.-Overview:...

    ) occurs in about 20% of women with ovulatory dysfunction.
  2. Infrequent and light menstruations occur in about 40% of women with ovulatory dysfunction.
  3. Irregular menstruation, where five or more menstrual cycles a year are five or more days shorter or longer than the length of the average cycle.
  4. Absence of mastodynia (breast pain or tenderness) occurs in about 20% of women with ovulatory problems.
  5. Increased body and facial hair (this is relatively easy to treat, and is often associated with PCOS, or polycystic ovary syndrome).

Fertility awareness and LH measurement

Symptoms-based methods of fertility awareness
Fertility awareness
Fertility awareness refers to a set of practices used to determine the fertile and infertile phases of a woman's menstrual cycle. Fertility awareness methods may be used to avoid pregnancy, to achieve pregnancy, or as a way to monitor gynecological health....

 may be used to detect ovulation or to determine that cycles are anovulatory. Charting of the menstrual cycle may be done by hand, or with the aid of various fertility monitors. Records of one of the primary fertility awareness signs—basal body temperature
Basal body temperature
Basal body temperature is the lowest temperature attained by the body during rest . It is generally measured immediately after awakening and before any physical activity has been undertaken, although the temperature measured at that time is somewhat higher than the true basal body temperature...

—can detect ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...

 by identifying the shift in temperature which takes place after ovulation. It is said to be the most reliable way of confirming whether ovulation has occurred.

Women may also use ovulation predictor kits (OPKs) with detect the increase in luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...

 (LH) levels that usually indicates imminent ovulation. For some women, these devices do not detect the LH surge, or high levels of LH are a poor predictor of ovulation; this is particularly common in women with PCOS. In such cases, OPKs and those fertility monitors which are based on LH may show false results, with an increased number of false positives or false negatives
Type I and type II errors
In statistical test theory the notion of statistical error is an integral part of hypothesis testing. The test requires an unambiguous statement of a null hypothesis, which usually corresponds to a default "state of nature", for example "this person is healthy", "this accused is not guilty" or...

. Dr Freundl from the University of Heidelberg suggests that tests which use LH as a reference often lack sensitivity and specificity.

Treatments

Treatments available to induce ovulation are usually quite efficient. The European Society of Human Reproduction and Embryology
European Society of Human Reproduction and Embryology
The European Society of Human Reproduction and Embryology was founded in 1985 by Robert Edwards and J. Cohen , who felt that the study and research in the field of reproduction needed to be encouraged and recognized.- Aims :...

 (ESHRE) notes that the aim of ovulation induction should be mono-ovulation and not over-stimulation of the ovaries . The risks associated with multiple pregnancies are much higher than singleton pregnancy; incidences of perinatal death are seven times higher in triplet births and five times higher in twin births than the risks associated with a singleton pregnancy. It is therefore important to adapt the treatment to each individual patient.
  1. The medication which is most commonly used to treat anovulation is clomifene citrate (or clomid). It is relatively easy and convenient to use. Clomifene appears to inhibit estrogen receptor
    Estrogen receptor
    Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...

    s in hypothalamus
    Hypothalamus
    The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

    , thereby inhibiting negative feedback
    Negative feedback
    Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...

     of estrogen on gonadotropin
    Gonadotropin
    Gonadotropins are protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. This is a family of proteins, which include the mammalian hormones follitropin , lutropin , placental chorionic gonadotropins hCG and eCG and chorionic gonadotropin , as well as at least two...

     production. It may also result in direct stimulation of the hypothalamic-pituitary axis. It also has an effect on cervical mucus quality and uterine mucosa, which might affect sperm
    Sperm
    The term sperm is derived from the Greek word sperma and refers to the male reproductive cells. In the types of sexual reproduction known as anisogamy and oogamy, there is a marked difference in the size of the gametes with the smaller one being termed the "male" or sperm cell...

     penetration and survival, hence its early administration during the menstrual cycle
    Menstrual cycle
    The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle....

    . Clomifene citrate is a very efficient ovulation inductor, and has a success rate of 67%. Nevertheless, it only has a 37% success rate in inducing pregnancy. This difference may be due to the anti-estrogenic effect which clomifene citrate has on the endometrium
    Endometrium
    -Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...

    , cervical mucus, uterine blood flow, as well as the resulting decrease in the motility of the fallopian tubes and the maturation of the oocytes.
  2. Another anti-estrogenic molecule called tamoxifen
    Tamoxifen
    Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...

     is often used in the prevention and treatment of breast cancer
    Breast cancer
    Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

    . It can therefore also be used to treat patients that have a reaction to clomifene citrate.
  3. Human chorionic gonadotropin
    Human chorionic gonadotropin
    Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...

     (hCG) is a molecule which is structurally similar to luteinizing hormone
    Luteinizing hormone
    Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...

     (LH). LH is secreted by the pituitary just before ovulation occurs, whereas hCG is released during pregnancy. On its own, hCG is not very effective in inducing ovulation, but when combined with clomifene citrate, it is much more effective. The results associated with this method have been described as "quite encouraging". HCG should only be administered at certain points in the cycle, around the time of ovulation, and only if the infertility diagnostic has indicated that the problem is related to the release of the egg.
  4. Human menopausal gonadotropin (hMG) is a very powerful treatment for infertility
    Infertility
    Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...

    . It consists of a combination of LH and FSH. From menopause onwards, the body starts secreting LH and FSH in large quantities due to the slowing down of the ovarian function. This excess of hormones is not used by the body and is expelled in the urine. HMG is therefore collected from the urine of menopausal women. The urine then undergoes purification and a chemical treatment. The resulting hMG induces the stimulation of several ovarian follicle
    Ovarian follicle
    Ovarian follicles are the basic units of female reproductive biology, each of which is composed of roughly spherical aggregations of cells found in the ovary. They contain a single oocyte . These structures are periodically initiated to grow and develop, culminating in ovulation of usually a single...

    s. This increases the risk of producing several oocytes during the same cycle, and thus the risk of multiple pregnancies.
  5. Follicle-stimulating hormone
    Follicle-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 or recombinant FSH) is now used as a replacement for hMG. Although hMG is a combination of FSH and LH, FSH is the only active component that has an effect on ovulation. However, until recently, it was not possible to produce pure FSH. FSH is now administered in a similar way as hMG, at a specific point during the cycle, and it requires medical monitoring. It is therefore important to fully understand a woman’s cycle, and to be able to accurately anticipate menstruation and ovulation dates. FSH is also sometimes useful for women who are suffering from PCOS.
  6. The gonadotropin-releasing hormone
    Gonadotropin-releasing hormone
    Gonadotropin-releasing hormone , also known as Luteinizing-hormone-releasing hormone and luliberin, is a tropic peptide hormone responsible for the release of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary. GnRH is synthesized and released from neurons within...

     (GnRH) pump is used to release doses of GnRH in a pulsatile fashion. This hormone is synthesised by the hypothalamus
    Hypothalamus
    The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

     and induces the secretion of LH and FSH by the pituitary. GnRH must be delivered in a pulsatile fashion to imitate the random secretion of the hypothalamus in order to fool the pituitary into secreting LH and FSH. The GnRH pump is the size of a cigarette box and has a small catheter. Unlike other treatments, using the GnRH pump doesn’t usually lead to multiple pregnancies. Dr. Filicori from the University of Bologna suggests that this might be because gonadotrophins are absent when the treatment is initiated, and therefore the hormones released by the pituitary (LH and FSH) can still take part in the retro-control of gonadotrophin secretion, mimicking the natural cycle. This treatment can also be used for underweight and/or anorexic patients; it has also been used in certain cases of hyperprolactimenia.
  7. Bromocriptine acts in a completely different manner to the other treatments mentioned above. It does not induce ovulation, but reduces the production of prolactin
    Prolactin
    Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...

     by the pituitary. Bromocriptine is only prescribed in cases of overproduction of prolactin (hyperprolactinemia).
  8. Corticosteroids (usually found in anti-inflammatory drugs) can be used to treat anovulation if it is caused by an overproduction of male hormones by the adrenal glands. Corticosteroids are usually used to reduce the production of testosterone
    Testosterone
    Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...

    .
  9. Several studies indicate that in some cases, a simple change in lifestyle could help patients suffering from anovulation. Consulting a nutritionist, for example, could help a young women suffering from anorexia to put on some weight, which might re-start her menstrual cycle
    Menstrual cycle
    The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle....

    . Conversely, a young overweight woman who manages to lose weight could also relieve the problem of anovulation (losing just 5% of body mass could be enough to re-start ovulation). However, it is widely acknowledged by doctors that it is usually very difficult for PCOS patients to lose weight.


Previously, metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...

 was recommended as treatment for anovulation in polycystic ovary syndrome, but in the largest trial to date, comparing clomiphene with metformin, clomiphene was more effective than metformin alone. Following this study, the ESHRE/ASRM-sponsored Consensus workshop do not recommend metformin for ovulation stimulation. Subsequent randomized studies have confirmed the lack of evidence for adding metformin to clomiphene.

Associated conditions

For most women, alteration of menstrual periods
Menstrual cycle
The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle....

 is the principal indication of chronic anovulation. Ovulatory menstrual periods tend to be regular and predictable in terms of cycle length, duration and heaviness of bleeding, and other symptoms. Ovulatory periods are often accompanied by midcycle symptoms such as mittelschmerz
Mittelschmerz
Mittelschmerz is a medical term for "ovulation pain" or "midcycle pain". About 20% of women experience mittelschmerz, some every cycle, some intermittently.-Symptoms and diagnosis:...

 or premenstrual symptoms. In contrast, anovulation usually manifests itself as irregularity of menstrual periods, that is, unpredictable variability of intervals, duration, or bleeding. Anovulation can also cause cessation of periods (secondary amenorrhea) or excessive bleeding (dysfunctional uterine bleeding
Dysfunctional uterine bleeding
Dysfunctional Uterine Bleeding is abnormal genital tract bleeding based in the uterus and found in the absence of demonstrable structural or organic pathology.usually due to hormonal disturbances....

). Mittelschmerz
Mittelschmerz
Mittelschmerz is a medical term for "ovulation pain" or "midcycle pain". About 20% of women experience mittelschmerz, some every cycle, some intermittently.-Symptoms and diagnosis:...

and premenstrual symptoms tend to be absent or reduced when a woman is anovulatory.
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