Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. 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.
Signs and symptomsEdit
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 menstruation occurs in about 40% of women with ovulatory dysfunction. Another potential symptom is 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. Also possible is increased body mass and facial hair, which is relatively easy to treat, and is often associated with PCOS, or polycystic ovary syndrome.
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.
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 ensure the development of an ovule, possibly due to 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, including the ovaries. This occurs in around 10% of cases. The mammary glands are also controlled by the pituitary gland, so lactation can also be affected. The pituitary gland is controlled by the hypothalamus. In 10% of 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-thyroidism 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.
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. 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). 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. Up to 90% of cases of anovulation are caused by PCOS; this syndrome is usually hereditary.
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. Unfortunately, not only does excess weight have a negative impact on ovulation itself, but also on treatment efficacy and outcomes of ART (assisted reproductive technique).
Fertility awareness and LH measurementEdit
Symptoms-based methods of fertility awareness 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.
Women may also use ovulation predictor kits (OPKs) which 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.
The World Health Organization criteria for classification of anovulation include the determination of oligomenorrhea (menstrual cycle >35 days) or amenorrea (menstrual cycle > 6 months) in combination with concentration of prolactin, follicle stimulating hormone (FSH) and estradiol (E2). The patients are classified as WHO1 (15%) - hypo-gonadotropic, hypo-estrogenic, WHO2 (80%) - normo-gonadotropic, normo-estrogenic, and WHO3 (5%) - hyper-gonadotropic, hypo-estrogenic. The vast majority of anovulation patients belong to the WHO2 group and demonstrate very heterogeneous symptoms ranging from anovulation, obesity, biochemical or clinical hyperandrogenism and insulin resistance.
Anovulation can potentially be reversed by lifestyle changes.
In otherwise healthy women with anovulation, avulatory disorders may be favorably influenced by a healthy diet such as a higher consumption of monounsaturated fats rather than trans fats, vegetable rather than animal protein sources, high fat dairy, multivitamins, and iron from plants and supplements.
The main alternatives for ovulation induction medications are:
- Antiestrogen, causing an inhibition of the negative feedback of estrogen on the pituitary gland, resulting in an increase in secretion of follicle-stimulating hormone. Medications in use for this effect are mainly clomifene citrate and tamoxifen (both being selective estrogen-receptor modulators), as well as letrozole (an aromatase inhibitor.
- Follicle-stimulating hormone (FSH), directly stimulating the ovaries. In women with anovulation, it may be an alternative after 7 - 12 attempted cycles of pituitary feedback regimens (as evidenced by clomifene citrate), since the latter ones are less expensive and more easy to control.
In vitro fertilizationEdit
The standard procedure of in vitro fertilization includes controlled ovarian hyperstimulation with gonadotropins, but in larger doses, with the intention to induce development of supernumerary follicles. This is followed by transvaginal oocyte retrieval, co-incubation and then embryo transfer of a safe number of follicles, which in international guidelines is no more than two.
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. 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.
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 woman suffering from anorexia to put on some weight, which might restart 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 restart ovulation). However, it is widely acknowledged by doctors that it is usually very difficult for PCOS patients to lose weight.
Previously, metformin 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.
- Legro RS (February 2007). "A 27-year-old woman with a diagnosis of polycystic ovary syndrome". JAMA. 297 (5): 509–519. doi:10.1001/jama.297.5.509. PMID 17284701.
- Alexander NB, Cotanch PH (September 1980). "The endocrine basis of infertility in women". Nurs. Clin. North Am. 15 (3): 511–24. PMID 6777763.
- Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (January 2004). "Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome". Fertil. Steril. 81 (1): 19–25. doi:10.1016/j.fertnstert.2003.10.004. PMID 14711538.
- Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO (June 2004). "The prevalence and features of the polycystic ovary syndrome in an unselected population". J. Clin. Endocrinol. Metab. 89 (6): 2745–2749. doi:10.1210/jc.2003-032046. PMID 15181052.
- Hull MG (September 1987). "Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies". Gynecol. Endocrinol. 1 (3): 235–245. doi:10.3109/09513598709023610. PMID 3140583.
- Barbieri RL (November 2001). "The initial fertility consultation: recommendations concerning cigarette smoking, body mass index, and alcohol and caffeine consumption". Am. J. Obstet. Gynecol. 185 (5): 1168–1173. doi:10.1067/mob.2001.117667. PMID 11717652.
- Filicori M, Flamigni C, Dellai P, et al. (October 1994). "Treatment of anovulation with pulsatile gonadotropin-releasing hormone: prognostic factors and clinical results in 600 cycles". J. Clin. Endocrinol. Metab. 79 (4): 1215–1220. doi:10.1210/jc.79.4.1215. PMID 7962297.
- Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC (July 1998). "Predictors of patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility". J. Clin. Endocrinol. Metab. 83 (7): 2361–2365. doi:10.1210/jc.83.7.2361. PMID 9661609.
- Hamilton-Fairley D, Kiddy D, Watson H, Paterson C, Franks S (February 1992). "Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotrophin". Br J Obstet Gynaecol. 99 (2): 128–31. doi:10.1111/j.1471-0528.1992.tb14470.x. PMID 1554664.
- Crosignani PG, Ragni G, Parazzini F, Wyssling H, Lombroso G, Perotti L (March 1994). "Anthropometric indicators and response to gonadotrophin for ovulation induction". Hum. Reprod. 9 (3): 420–3. doi:10.1093/oxfordjournals.humrep.a138521. PMID 8006129.
- Fedorcsák P, Storeng R, Dale PO, Tanbo T, Abyholm T (January 2000). "Obesity is a risk factor for early pregnancy loss after IVF or ICSI". Acta Obstet Gynecol Scand. 79 (1): 43–48. doi:10.1080/j.1600-0412.2000.079001043.x. PMID 10646815.[permanent dead link]
- Freundl G; Godehardt E; Kern PA; Frank-Herrmann P; Koubenec HJ; Gnoth Ch (December 2003). "Estimated maximum failure rates of cycle monitors using daily conception probabilities in the menstrual cycle". Hum. Reprod. 18 (12): 2628–2633. doi:10.1093/humrep/deg488. PMID 14645183.
- Freundl G, Bremme M, Frank-Herrmann P, Baur S, Godehardt E, Sottong U (June 1996). "The CUE Fertility Monitor compared to ultrasound and LH peak measurements for fertile time ovulation detection". Adv Contracept. 12 (2): 111–121. doi:10.1007/BF01849632. PMID 8863906.
- NADIR R. FARID; Evanthia Diamanti-Kandarakis (26 March 2009). Diagnosis and Management of Polycystic Ovary Syndrome. Springer. p. 243. ISBN 978-0-387-09717-6. Retrieved 5 September 2012.
- Chavarro, Jorge E.; Rich-Edwards, Janet W.; Rosner, Bernard A.; Willett, Walter C. (2007). "Diet and Lifestyle in the Prevention of Ovulatory Disorder Infertility". Obstetrics & Gynecology. 110 (5): 1050–1058. doi:10.1097/01.AOG.0000287293.25465.e1. ISSN 0029-7844.
- Hamilton-Fairley, D. (2003). "Anovulation". BMJ. 327 (7414): 546–549. doi:10.1136/bmj.327.7414.546. ISSN 0959-8138. PMC 192851.
- Elshamy, Elsayed; Khalafallah, Mohammed (2018). "Impact of clomiphene citrate, tamoxifen and letrozole to induce ovulation in anovulatory women with polycystic ovary syndrome on endometrial thickness and clinical pregnancy rates, a two center cohort study". Obstetrics & Gynecology International Journal. 9 (4). doi:10.15406/ogij.2018.09.00344. ISSN 2377-4304.
- Weiss, N. S.; Braam, S.; Konig, T. E.; Hendriks, M. L.; Hamilton, C. J.; Smeenk, J. M. J.; Koks, C. A. M.; Kaaijk, E. M.; Hompes, P. G. A.; Lambalk, C. B.; van der Veen, F.; Mol, B. W. J.; van Wely, M. (2014). "How long should we continue clomiphene citrate in anovulatory women?". Human Reproduction. 29 (11): 2482–2486. doi:10.1093/humrep/deu215. ISSN 0268-1161.
- Fertility: assessment and treatment for people with fertility problems. NICE clinical guideline CG156 - Issued: February 2013
- Palomba S, Orio F, Nardo LG, et al. (October 2004). "Metformin administration versus laparoscopic ovarian diathermy in clomiphene citrate-resistant women with polycystic ovary syndrome: a prospective parallel randomized double-blind placebo-controlled trial". J. Clin. Endocrinol. Metab. 89 (10): 4801–4809. doi:10.1210/jc.2004-0689. PMID 15472166.
- Legro RS, Barnhart HX, Schlaff WD (2007). "Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome". N Engl J Med. 356 (6): 551–566. doi:10.1056/NEJMoa063971. PMID 17287476.
- Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (March 2008). "Consensus on infertility treatment related to polycystic ovary syndrome". Fertil. Steril. 89 (3): 505–522. doi:10.1016/j.fertnstert.2007.09.041. PMID 18243179.
- Johnson NP, Stewart AW, Falkiner J, et al. (April 2010). "PCOSMIC: a multi-centre randomized trial in women with PolyCystic Ovary Syndrome evaluating Metformin for Infertility with Clomiphene". Hum Reprod. 25 (7): 1675–1683. doi:10.1093/humrep/deq100. PMID 20435692.