Anovulation

Infobox_Disease
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Caption =
DiseasesDB =
ICD10 = ICD10|N|97|0|n|80
ICD9 = ICD9|628.0
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eMedicineSubj = med
eMedicineTopic = 146
MeshID = D000858An anovulatory cycle is a cycle during which the ovaries fail to release an oocyte. 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.

In addition to the alteration of menstrual periods and infertility, chronic anovulation can cause or exacerbate other long term problems, such as hyperandrogenism or osteopenia. It plays a central role in the multiple imbalances and dysfunctions of polycystic ovary syndrome.

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.

Causes

Hormonal or chemical imbalance

This is the most common cause of anovulation and is thought to account for about 70% of all cases.

# About half the women with hormonal imbalances do not produce enough follicles to insure the development of an ovule. This could be caused by poor hormonal secretions from the pituitary gland or the hypothalamus.
# The pituitary gland controls most other hormonal glands in the human body. Therefore, any pituitary malfunctioning affects other glands under its influence, of which the ovaries. This occurs in around 10% of the cases. Mammary glands are also controlled by the pituitary gland, which can thus also affect lactation.
# The hypothalamus controls the pituitary gland. In 10% of the cases, alterations in the chemical signals from the hypothalamus can easily seriously affect the ovaries.
# There are other hormonal anomalies with no direct link to the ones mentioned above that can affect ovulation. For instance, women with hyper or hypo-thyrodism sometimes have ovulation problems. Thyroid dysfunction can halt ovulation by upsetting the balance of the body’s natural reproductive hormones. Polycystic ovary syndrome (also known as Stein-Leventhal syndrome) and hyperprolactinemia can also cause anovulatory cycles through hormonal imbalances. [cite journal |author=Legro RS |title=A 27-year-old woman with a diagnosis of polycystic ovary syndrome |journal=JAMA |volume=297 |issue=5 |pages=509–19 |year=2007 |month=February |pmid=17284701 |doi=10.1001/jama.297.5.509] [cite journal |author=Alexander NB, Cotanch PH |title=The endocrine basis of infertility in women |journal=Nurs. Clin. North Am. |volume=15 |issue=3 |pages=511–24 |year=1980 |month=September |pmid=6777763 ]

Functional problem

This accounts for around 10-15% of all cases of anovulation.

# 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. Blocked ovaries can start functioning again without a clear medical explanation.
# A significant emotional shock can temporarily affect the functioning of the brain and can lead to dysfunction of the hypothalamus. However, this is not as common as people might think.
# In some cases, the egg may have matured properly, but the follicle may have failed to burst (or the follicle may have burst without releasing the egg). This is called luteinised unruptured follicle syndrome (LUFS). Dr Letouzey from the Arnaud-de-Villeneuve Hospital (CHU) has described the case of a couple with this disorder who goes through IVF, and discusses the different approaches that one might consider for such a diagnosis. [cite journal |author=Letouzey V, Reyftmann L, Hamamah S, Hédon B |title=Pregnancy results in in vitro fertilization in one case of luteinized-unruptured-follicle syndrome |language=French |journal=Gynecol Obstet Fertil |volume=36 |issue=1 |pages=60–2 |year=2008 |month=January |pmid=18248842 |doi=10.1016/j.gyobfe.2007.10.022 ]
# Physical damage to the ovaries, or ovaries with multiple cysts, may affect their ability to function. This is called ovarian dystrophy. Patients who are suffering from Stein-Leventhal syndrome (also referred to as polycystic ovary syndrome, or PCOS) can also suffer from anovulation. [cite journal |author= |title=Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome |journal=Fertil. Steril. |volume=81 |issue=1 |pages=19–25 |year=2004 |month=January |pmid=14711538 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S001502820302853X] Up to 90% of cases of anovulation are caused by PCOS; this syndrome is usually hereditary. [cite journal |author=Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO |title=The prevalence and features of the polycystic ovary syndrome in an unselected population |journal=J. Clin. Endocrinol. Metab. |volume=89 |issue=6 |pages=2745–9 |year=2004 |month=June |pmid=15181052 |doi=10.1210/jc.2003-032046] [cite journal |author=Hull MG |title=Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies |journal=Gynecol. Endocrinol. |volume=1 |issue=3 |pages=235–45 |year=1987 |month=September |pmid=3140583]
# Weight loss or anorexia 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) over 27 ^kg/_m2. [cite journal |author=Barbieri RL |title=The initial fertility consultation: recommendations concerning cigarette smoking, body mass index, and alcohol and caffeine consumption |journal=Am. J. Obstet. Gynecol. |volume=185 |issue=5 |pages=1168–73 |year=2001 |month=November |pmid=11717652 |doi=10.1067/mob.[phone] ] cite journal |author=Filicori M, Flamigni C, Dellai P, "et al" |title=Treatment of anovulation with pulsatile gonadotropin-releasing hormone: prognostic factors and clinical results in 600 cycles |journal=J. Clin. Endocrinol. Metab. |volume=79 |issue=4 |pages=1215–20 |year=1994 |month=October |pmid=7962297 |doi= |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=7962297] [cite journal |author=Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC |title=Predictors of patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility |journal=J. Clin. Endocrinol. Metab. |volume=83 |issue=7 |pages=2361–5 |year=1998 |month=July |pmid=9661609 |doi= |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=9661609] Unfortunately, not only does excess weight have a negative impact on ovulation itself, [cite journal |author=Hamilton-Fairley D, Kiddy D, Watson H, Paterson C, Franks S |title=Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotrophin |journal=Br J Obstet Gynaecol |volume=99 |issue=2 |pages=128–31 |year=1992 |month=February |pmid=1554664] but also on treatment efficacy and outcomes of ART (assisted reproductive technique). [cite journal |author=Crosignani PG, Ragni G, Parazzini F, Wyssling H, Lombroso G, Perotti L |title=Anthropometric indicators and response to gonadotrophin for ovulation induction |journal=Hum. Reprod. |volume=9 |issue=3 |pages=420–3 |year=1994 |month=March |pmid=8006129 |doi= |url=http://humrep.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8006129] [cite journal |author=Fedorcsák P, Storeng R, Dale PO, Tanbo T, Abyholm T |title=Obesity is a risk factor for early pregnancy loss after IVF or ICSI |journal=Acta Obstet Gynecol Scand |volume=79 |issue=1 |pages=43–8 |year=2000 |month=January |pmid=10646815 |doi= |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0001-6349&date=2000&volume=79&issue=1&spage=43-8]

Detection

igns and symptoms

Anovulation is usually associated with specific symptoms. However, it is important to note that they are not necessarily all displayed simultaneously.

# Amenorrhea (absence of menstruation) occurs in about 20% of women with ovulatory dysfunction.
# Infrequent and light menstruations occur in about 40% of women with ovulatory dysfunction.
# 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.
# Absence of mastodynia (breast pain or tenderness) occurs in about 20% of women with ovulatory problems.
# 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 methods 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—can detect ovulation 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. [cite journal |author=Freundl G, Godehardt E, Kern PA, Frank-Herrmann P, Koubenec HJ, Gnoth Ch |title=Estimated maximum failure rates of cycle monitors using daily conception probabilities in the menstrual cycle |journal=Hum. Reprod. |volume=18 |issue=12 |pages=2628–33 |year=2003 |month=December |pmid=14645183 |doi= |url=http://humrep.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=14645183]

Women may also use ovulation predictor kits (OPKs) with detect the increase in luteinizing hormone (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. Dr Freundl from the University of Heidelberg suggests that tests which use LH as a reference often lack sensitivity and specificity. [cite journal |author=Freundl G, Bremme M, Frank-Herrmann P, Baur S, Godehardt E, Sottong U |title=The CUE Fertility Monitor compared to ultrasound and LH peak measurements for fertile time ovulation detection |journal=Adv Contracept |volume=12 |issue=2 |pages=111–21 |year=1996 |month=June |pmid=8863906]

Treatments

Treatments available to induce ovulation are usually quite efficient. Ovaries are relatively easy to stimulate and in 90% of cases, ovulation can be induced thanks to a suitable medication. The European Society of Human Reproduction and Embryology (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. [cite journal |author=Bergh T, Ericson A, Hillensjö T, Nygren KG, Wennerholm UB |title=Deliveries and children born after in-vitro fertilisation in Sweden 1982-95: a retrospective cohort study |journal=Lancet |volume=354 |issue=9190 |pages=1579–85 |year=1999 |month=November |pmid=10560671 |doi=10.1016/S0140-6736(99)04345-7] [cite journal |author=Fisk NM, Trew G |title=Two's company, three's a crowd for embryo transfer |journal=Lancet |volume=354 |issue=9190 |pages=1572–3 |year=1999 |month=November |pmid=10560665 |doi=10.1016/S0140-6736(99)00290-1] It is therefore important to adapt the treatment to each individual patient. [cite journal |author= |title=Mono-ovulatory cycles: a key goal in profertility programmes |journal=Hum. Reprod. Update |volume=9 |issue=3 |pages=263–74 |year=2003 |pmid=12859047 |doi= |url=http://humupd.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12859047]

#The medication which is most commonly used to treat anovulation is clomifene citrate (or clomid), which has been used since the 1960s. [cite journal |author=HOLTKAMP DE, GRESLIN JG, ROOT CA, LERNER LJ |title=Gonadotrophin inhibiting and anti-fecundity effects of chloramiphene |journal=Proc. Soc. Exp. Biol. Med. |volume=105 |issue= |pages=197–201 |year=1960 |month=October |pmid=13715563] It was first used to treat cases of oligomenorrhea, and it was then applied to the treatment of anovulation. [cite journal |author=Hughes E, Collins J, Vandekerckhove P |title=Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea |journal=Cochrane Database Syst Rev |volume= |issue=2 |pages=CD000056 |year=2000 |pmid=10796477 |doi=10.1002/14651858.CD000056] It is relatively easy and convenient to use: factors which contributed to its success.cite journal |author=Lord JM, Flight IH, Norman RJ |title=Metformin in polycystic ovary syndrome: systematic review and meta-analysis |journal=BMJ |volume=327 |issue=7421 |pages=951–3 |year=2003 |month=October |pmid=14576245 |pmc=259161 |doi=10.1136/bmj.327.7421.951] Clomifene citrate has an anti-estrogenic role, and it appears to stimulate the pituitary and therefore affect the ovarian function. [cite journal |author=Adashi EY |title=Clomiphene citrate: mechanism(s) and site(s) of action--a hypothesis revisited |journal=Fertil. Steril. |volume=42 |issue=3 |pages=331–44 |year=1984 |month=September |pmid=6432584] It also has an effect on cervical mucus quality and uterine mucosa, which might affect sperm penetration and survival, hence its early administration during the 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. Dr. Kousta from Imperial College, London explains that this difference may be due to the anti-estrogenic effect which clomifene citrate has on the endometrium, cervical mucus, uterine blood flow, as well as the resulting decrease in the motility of the fallopian tubes and the maturation of the oocytes. [cite journal |author=Kousta E, White DM, Franks S |title=Modern use of clomiphene citrate in induction of ovulation |journal=Hum. Reprod. Update |volume=3 |issue=4 |pages=359–65 |year=1997 |pmid=9459281 |doi= |url=http://humupd.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9459281]
# Another anti-estrogenic molecule called tamoxifen is often used in the prevention and treatment of breast cancer. It can therefore also be used to treat patients that have a reaction to clomifene citrate. [cite journal |author=Boostanfar R, Jain JK, Mishell DR, Paulson RJ |title=A prospective randomized trial comparing clomiphene citrate with tamoxifen citrate for ovulation induction |journal=Fertil. Steril. |volume=75 |issue=5 |pages=1024–6 |year=2001 |month=May |pmid=11334921 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0015-0282(01)01749-6]
# Human chorionic gonadotropin (hCG) is a molecule which is structurally similar to luteinizing hormone (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". [cite journal |author=Nugent D, Vandekerckhove P, Hughes E, Arnot M, Lilford R |title=Gonadotrophin therapy for ovulation induction in subfertility associated with polycystic ovary syndrome |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD000410 |year=2000 |pmid=11034687 |doi=10.1002/14651858.CD000410 |url=] 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.
# Human menopausal gonadotropin (hMG) is a very powerful treatment for infertility. 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 follicles. This increases the risk of producing several oocytes during the same cycle, and thus the risk of multiple pregnancies.
# Follicle-stimulating hormone (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.
# The gonadotropin-releasing hormone (GnRH) pump is used to release doses of GnRH in a pulsatile fashion. This hormone is synthesised by the hypothalamus 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 due to the fact that 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; [cite journal |author=Braat DD, Schoemaker R, Schoemaker J |title=Life table analysis of fecundity in intravenously gonadotropin-releasing hormone-treated patients with normogonadotropic and hypogonadotropic amenorrhea |journal=Fertil. Steril. |volume=55 |issue=2 |pages=266–71 |year=1991 |month=February |pmid=1991525] it has also been used in certain cases of hyperprolactimenia.
# Bromocriptine acts in a completely different manner to the other treatments mentioned above. It does not induce ovulation, but reduces the production of prolactin by the pituitary.cite journal |author=Palomba S, Orio F, Nardo LG, "et al" |title=Metformin administration versus laparoscopic ovarian diathermy in clomiphene citrate-resistant women with polycystic ovary syndrome: a prospective parallel randomized double-blind placebo-controlled trial |journal=J. Clin. Endocrinol. Metab. |volume=89 |issue=10 |pages=4801–9 |year=2004 |month=October |pmid=15472166 |doi=10.1210/jc.2004-0689] Bromocriptine is only prescribed in cases of overproduction of prolactin (hyperprolactinemia).
# 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.
# Metformin is an oral biguanid used to treat type 2 diabetes that has shown very promising results in the treatment of patients with PCOS.cite journal |author=Kashyap S, Wells GA, Rosenwaks Z |title=Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome |journal=Hum. Reprod. |volume=19 |issue=11 |pages=2474–83 |year=2004 |month=November |pmid=15358717 |doi=10.1093/humrep/deh440] [cite journal |author=Costello MF, Eden JA |title=A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome |journal=Fertil. Steril. |volume=79 |issue=1 |pages=1–13 |year=2003 |month=January |pmid=12524053 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0015028202045545] [cite journal |author=Harborne L, Fleming R, Lyall H, Norman J, Sattar N |title=Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome |journal=Lancet |volume=361 |issue=9372 |pages=1894–901 |year=2003 |month=May |pmid=12788588 |doi=10.1016/S0140-6736(03)13493-9] Dr. Palomba from the University of "Magna Graecia" of Catanzaro indicates that the results after 6 cycles of metformin treatment are better than treatment with clomifene citrate for non-obese PCOS patients. [cite journal |author=Palomba S, Orio F, Falbo A, "et al" |title=Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome |journal=J. Clin. Endocrinol. Metab. |volume=90 |issue=7 |pages=4068–74 |year=2005 |month=July |pmid=15840746 |doi=10.1210/jc.2005-0110] However, some experts question the efficacy of metformin; further studies need to be conducted before its real efficacy can be assessed. Prof. Adam Balen from the Leeds General Infirmary notes that even though the results from early treatment with metformin were promising, its role and the roles of other similar molecules in reducing insulin levels among patients suffering from PCOS is not very clear. [cite journal |author=Balen AH, Rutherford AJ |title=Managing anovulatory infertility and polycystic ovary syndrome |journal=BMJ |volume=335 |issue=7621 |pages=663–6 |year=2007 |month=September |pmid=17901517 |pmc=1995495 |doi=10.1136/bmj.39335.462303.80] A recent study indicates that treatment with metformin is more appropriate than ovarian diathermia. Metformin can also be administered together with clomifene citrate and in this case its efficacy is 3.5 times better than that of a placebo.
# 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. 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.

Associated conditions

For most women, alteration of menstrual periods 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 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). Mittelschmerz and premenstrual symptoms tend to be absent or reduced when a woman is anovulatory.

References