Anovulation

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Anovulation
Specialty Gynecology

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.

Contents

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 anovulatory cycles.

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, women 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 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 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.

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.

Causes

Hormonal imbalance 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 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 hypothyroidism sometimes have ovulation problems. Thyroid dysfunction can halt ovulation by upsetting the balance of the body's natural reproductive hormones.

Currently, the four main causes of ovulatory disorders are polycystic ovarian syndrome (PCOS), hypogonadotropic hypogonadism (HA), primary ovarian insufficiency (POI), and hyperprolactinemia. [1]

Polycystic ovarian syndrome

Women with PCOS make up the greatest portion of anovulatory women in clinical practice. The criteria for a PCOS diagnosis is referred to as the Rotterdam criteria and consists of

  1. oligoovulation and/or anovulation
  2. excess androgen activity
  3. polycystic ovaries (by gynecologic ultrasound) [2]

Hypogonadotropic hypogonadism

Hypothalamic causes of HA include functional hypothalamic amenorrhea (FHA) and isolated gonadotropin-releasing hormone (GnRH) deficiency. [3] Laboratory findings of low serum estradiol and low FSH are associated with the decrease in hypothalamic secretion of GnRH. [3]

A rare form of HA that presents as primary amenorrhea can be due to a congenital deficiency of GnRH knows as idiopathic hypogonadotropic hypogonadism or, Kallmann syndrome if it is associated with anosmia. [3] Infiltrative disease or tumors affecting the hypothalamus and pituitary can result in HA. [3]

FHA accounts for around 10–15% of all cases of anovulation. Weight loss or anorexia can lead to FHA by causing a 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.

Primary ovarian insufficiency

POI was previously referred to as premature ovarian failure (POF) and diagnosed when menopause occurred before age 40 but occurs in only 1 percent of all women. [4] 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 luteinized 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.

Hyperprolactinemia

Hyperprolactinemia anovulation makes up 5 to 10 percent of women with anovulation. Hyperprolactinemia inhibits gonadotropin secretion by inhibiting GnRH. [5] Hyperprolactinemia can be confirmed by several measurements of serum prolactin.

Diagnosis

Fertility awareness and LH measurement

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. [1]

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. [2]

Classification and testing

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. [3] This classification system does not include a separate category for anovulation caused by hyperprolactinemia, and experts do not consistently use this system.

Diagnosis of anovulation cause involves hormone level tests, in conjunction with an assessment of associated symptoms. A patient history and physical exam should include history of onset and pattern of oligomenorrhea or amenorrhea, signs of PCOS such as hyperandrogenism and obesity, eating disorders, causes of excessive physical or mental stress, and breast secretions. [6] [7] [8] Patients with symptoms of hyperandrogenism, such as hirsutism, can be tested for serum androgen levels as well as serum total testosterone levels. [6] A 17-hydroprogesterone test may also be conducted if congenital adrenal hyperplasia is suspected. If the differential is broad, hormone serum levels of estradiol, follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), anti-Müllerian hormone (AMH), thyroid-stimulating hormone (TSH), and prolactin can be diagnostic since most causes of anovulation are hormonal imbalances. [7] [8] [9] Transvaginal ultrasound may also be used to visualize polycystic ovaries. [6]

Treatments

Treatment should be based on diagnosis of anovulation. Treatment varies based on the 4 most common causes of anovulation: polycystic ovarian syndrome (PCOS), hypogonadotropic hypogonadism (HA), primary ovarian insufficiency (POI), and hyperprolactinemia. [10]  Importantly, semen analysis should be carried out of the XY partner to exclude severe XY factors before managing anovulatory subfertility. [10] Overall, in healthy individuals with anovulation, ovulatory 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. [4] [ non-primary source needed ]

Treatment for polycystic ovarian syndrome (PCOS)

Treatment for management of anovulation due to PCOS is multifaceted, including weight reduction, ovulation induction agents, insulin-sensitizing agents, gonadotrophins and ovarian drilling. In PCOS patients with overweight or obesity, weight loss is first line treatment. Studies show a reduction in weight as little of 5% by caloric restriction and increased physical activity can re-establish spontaneously ovulation and improve response to ovulation induction therapy if initiated. [11] [12] Weight loss also generally results in improved menstrual regularity and pregnancy rates in women with PCOS. [13]

It is well recognized that insulin resistance can be part of the sequelae of PCOS and if present, contribute to anovulation. Metformin, a biguanide, is a common insulin sensitizer often given to treat women with PCOS. [10] No other insulin sensitizers have evidence of effective and safe use of fertility treatment. [10] 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. [5] Following this study, the ESHRE/ASRM-sponsored A consensus workshop does not recommend metformin for ovulation stimulation. [14] Subsequent randomized studies have confirmed the lack of evidence for adding metformin to clomiphene. [15]

Ovulation induction

The main ovulation induction medications include:

Treatment for hypogonadotropic hypogonadism (HA)

In women with hypogonadotropic hypogonadism suspicious for functional hypothalamic amenorrhea, treatment should be centered around weight gain, reducing intensity and frequency of exercise, and stress reduction with psychotherapy or counseling. [10] Athletes and women with anorexia can have reduced GnRH pulsing due to hypothalamic dysfunction due to increased energy requirements without their needs being met calorically and severely reduced caloric intake, respectively. [17] If anovulation persists following lifestyle modifications, ovulation can be induced with pulsatile gonadotrophin-releasing hormone (GnRH) or gonadotrophin (FSH & LH) administration. [10]

Treatment for primary ovarian insufficiency (POI)

For women with POI that desire pregnancy, ovulation induction strategies should be avoided and assisted reproduction, such as in vitro fertilization (IVF) with donor oocytes, should be offered. [10]

Treatment for hyperprolactinemia

For anovulatory women with hyperprolactinemia without symptoms, they can forgo treatment and continue with close follow up and medical observation. [10] If symptoms of hyperprolactinemia are present, dopamine agonists, such as bromocriptine, are first line treatment which act by inhibiting production of prolactin by the pituitary and can shrink a prolactin-secretin lesion (i.e. prolactinoma) if present. [18] In rare cases, endoscopic transnasal transsphenoidal surgery and radiotherapy, may be required to resect and shrink a prolactinoma if greater than 10 mm in size. Importantly, individuals should be able to conceive following normalization of serum prolactin levels and shrinking or removal of the tumor. [10]

Other treatments

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.

Related Research Articles

<span class="mw-page-title-main">Polycystic ovary syndrome</span> Set of symptoms caused by abnormal hormones in females

Polycystic ovary syndrome, or polycystic ovarian syndrome (PCOS), is the most common endocrine disorder in women of reproductive age. The syndrome is named after cysts which form on the ovaries of some people with this condition, though this is not a universal symptom, and not the underlying cause of the disorder.

<span class="mw-page-title-main">Menstrual cycle</span> Natural changes in the human female reproductive system

The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eggs and the cyclic release of estrogen and progesterone. The uterine cycle governs the preparation and maintenance of the lining of the uterus (womb) to receive an embryo. These cycles are concurrent and coordinated, normally last between 21 and 35 days, with a median length of 28 days, and continue for about 30–45 years.

<span class="mw-page-title-main">Ovulation</span> Release of egg cells from the ovaries

Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized by sperm. In addition, the uterine lining (endometrium) is thickened to be able to receive a fertilized egg. If no conception occurs, the uterine lining as well as the egg will be shed during menstruation.

Amenorrhea is the absence of a menstrual period in a female who has reached reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses during childhood and after menopause.

<span class="mw-page-title-main">Hyperprolactinaemia</span> Medical condition

Hyperprolactinaemia is the presence of abnormally high levels of prolactin in the blood. Normal levels average to about 13 ng/mL in women, and 5 ng/mL in men, with an upper normal limit of serum prolactin levels being 15-25 ng/mL for both. When the fasting levels of prolactin in blood exceed this upper limit, hyperprolactinemia is indicated.

<span class="mw-page-title-main">Follicle-stimulating hormone</span> Gonadotropin that regulates the development of reproductive processes

Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system.

<span class="mw-page-title-main">Hyperandrogenism</span> Medical condition

Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea, hair loss on the scalp, increased body or facial hair, and infrequent or absent menstruation. Complications may include high blood cholesterol and diabetes. It occurs in approximately 5% of women of reproductive age.

The anovulatory cycle is a menstrual cycle by varying degrees of menstrual intervals and the absence of ovulation and a luteal phase. In the absence of ovulation, there will be infertility.

Fertility medications, also known as fertility drugs, are medications which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are very few fertility medication options available for men.

<span class="mw-page-title-main">Lactational amenorrhea</span> Post-partum infertility due to breast feeding

Lactational amenorrhea, also called postpartum infertility, is the temporary postnatal infertility that occurs when a woman is amenorrheic and fully breastfeeding.

<span class="mw-page-title-main">Menstrual disorder</span> Medical condition affecting menstrual cycle

A menstrual disorder is characterized as any abnormal condition with regards to a woman's menstrual cycle. There are many different types of menstrual disorders that vary with signs and symptoms, including pain during menstruation, heavy bleeding, or absence of menstruation. Normal variations can occur in menstrual patterns but generally menstrual disorders can also include periods that come sooner than 21 days apart, more than 3 months apart, or last more than 10 days in duration. Variations of the menstrual cycle are mainly caused by the immaturity of the hypothalamic-pituitary-ovarian (HPO) axis, and early detection and management is required in order to minimize the possibility of complications regarding future reproductive ability.

<span class="mw-page-title-main">Bone morphogenetic protein 15</span> Protein-coding gene in humans

Bone morphogenetic protein 15 (BMP-15) is a protein that in humans is encoded by the BMP15 gene. It is involved in folliculogenesis, the process in which primordial follicles develop into pre-ovulatory follicles.

Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles to reverse anovulation or oligoovulation.

Functional hypothalamic amenorrhea (FHA) is a form of amenorrhea and chronic anovulation and is one of the most common types of secondary amenorrhea. It is classified as hypogonadotropic hypogonadism. It was previously known as "juvenile hypothalamosis syndrome," prior to the discovery that sexually mature females are equally affected. FHA has multiple risk factors, with links to stress-related, weight-related, and exercise-related factors. FHA is caused by stress-induced suppression of the hypothalamic-pituitary-ovarian (HPO) axis, which results in inhibition of gonadotropin-releasing hormone (GnRH) secretion, and gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Severe and potentially prolonged hypoestrogenism is perhaps the most dangerous hormonal pathology associated with the disease, because consequences of this disturbance can influence bone health, cardiovascular health, mental health, and metabolic functioning in both the short and long-term. Because many of the symptoms overlap with those of organic hypothalamic, pituitary, or gonadal disease and therefore must be ruled out, FHA is a diagnosis of exclusion; "functional" is used to indicate a behavioral cause, in which no anatomical or organic disease is identified, and is reversible with correction of the underlying cause. Diagnostic workup includes a detailed history and physical, laboratory studies, such as a pregnancy test, and serum levels of FSH and LH, prolactin, and thyroid-stimulating hormone (TSH), and imaging. Additional tests may be indicated in order to distinguish FHA from organic hypothalamic or pituitary disorders. Patients present with a broad range of symptoms related to severe hypoestrogenism as well as hypercortisolemia, low serum insulin levels, low serum insulin-like growth factor 1 (IGF-1), and low total triiodothyronine (T3). Treatment is primarily managing the primary cause of the FHA with behavioral modifications. While hormonal-based therapies are potential treatment to restore menses, weight gain and behavioral modifications can have an even more potent impact on reversing neuroendocrine abnormalities, preventing further bone loss, and re-establishing menses, making this the recommended line of treatment. If this fails to work, secondary treatment is aimed at treating the effects of hypoestrogenism, hypercortisolism, and hypothyroidism.

Hypomenorrhea or hypomenorrhoea, also known as short or scanty periods, is extremely light menstrual blood flow. It is the opposite of heavy periods or hypermenorrhea which is more properly called menorrhagia.

Ovarian drilling, also known as multiperforation or laparoscopic ovarian diathermy, is a surgical technique of puncturing the membranes surrounding the ovary with a laser beam or a surgical needle using minimally invasive laparoscopic procedures. It differs from ovarian wedge resection, which involves the cutting of tissue. Minimally invasive ovarian drilling procedures have replaced wedge resections. Ovarian drilling is preferred to wedge resection because cutting into the ovary can cause adhesions which may complicate postoperative outcomes. Ovarian drilling and ovarian wedge resection are treatment options to reduce the amount of androgen producing tissue in women with polycystic ovarian syndrome (PCOS). PCOS is the primary cause of anovulation, which results in female infertility. The induction of mono-ovulatory cycles can restore fertility.

Infertility in polycystic ovary disease (PCOS) is a hormonal imbalance in women that is thought to be one of the leading causes of female infertility. Polycystic ovary syndrome causes more than 75% of cases of anovulatory infertility.

Obesity is defined as an abnormal accumulation of body fat, usually 20% or more over an individual's ideal body weight. This is often described as a body mass index (BMI) over 30. However, BMI does not account for whether the excess weight is fat or muscle, and is not a measure of body composition. For most people, however, BMI is an indication used worldwide to estimate nutritional status. Obesity is usually the result of consuming more calories than the body needs and not expending that energy by doing exercise. There are genetic causes and hormonal disorders that cause people to gain significant amounts of weight but this is rare. People in the obese category are much more likely to suffer from fertility problems than people of normal healthy weight.

Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anterior pituitary and the ovarian cycle. During the early to mid-follicular phase of the ovarian cycle, GnSAF acts on the anterior pituitary to attenuate LH release, limiting the secretion of LH to only basal levels. At the transition between follicular and luteal phase, GnSAF bioactivity declines sufficiently to permit LH secretion above basal levels, resulting in the mid-cycle LH surge that initiates ovulation. In normally ovulating women, the LH surge only occurs when the oocyte is mature and ready for extrusion. GnSAF bioactivity is responsible for the synchronised, biphasic nature of LH secretion.

Ovarian follicle dominance is the process where one or more follicles are selected per cycle to ovulate.

References

  1. 1 2 Hamilton-Fairley, Diana; Taylor, Alison (2003-09-06). "Anovulation". BMJ (Clinical Research Ed.). 327 (7414): 546–549. doi:10.1136/bmj.327.7414.546. ISSN   1756-1833. PMC   192851 . PMID   12958117.
  2. 1 2 Richard Scott Lucidi (25 October 2011). "Polycystic Ovarian Syndrome". eMedicine. Archived from the original on 10 November 2011. Retrieved 19 November 2011
  3. 1 2 3 4 5 Unuane, David; Tournaye, Herman; Velkeniers, Brigitte; Poppe, Kris (December 2011). "Endocrine disorders & female infertility". Best Practice & Research. Clinical Endocrinology & Metabolism. 25 (6): 861–873. doi:10.1016/j.beem.2011.08.001. ISSN   1878-1594. PMID   22115162.
  4. 1 2 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. PMID   17978119. S2CID   6719868.
  5. 1 2 Rebar, Robert (2000), Feingold, Kenneth R.; Anawalt, Bradley; Boyce, Alison; Chrousos, George (eds.), "Evaluation of Amenorrhea, Anovulation, and Abnormal Bleeding", Endotext, South Dartmouth (MA): MDText.com, Inc., PMID   25905367 , retrieved 2022-11-14
  6. 1 2 3 Teede, Helena J.; Misso, Marie L.; Costello, Michael F.; Dokras, Anuja; Laven, Joop; Moran, Lisa; Piltonen, Terhi; Norman, Robert. J. (August 2018). "Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome". Fertility and Sterility. 110 (3): 364–379. doi:10.1016/j.fertnstert.2018.05.004. ISSN   0015-0282. PMC   6939856 . PMID   30033227.
  7. 1 2 Gordon, Catherine M. (2010-07-16). "Functional Hypothalamic Amenorrhea". New England Journal of Medicine. 363 (4): 365–371. doi:10.1056/nejmcp0912024. PMID   20660404.
  8. 1 2 Casanueva, Felipe F.; Molitch, Mark E.; Schlechte, Janet A.; Abs, Roger; Bonert, Vivien; Bronstein, Marcello D.; Brue, Thierry; Cappabianca, Paolo; Colao, Annamaria; Fahlbusch, Rudolf; Fideleff, Hugo (2006). "Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas". Clinical Endocrinology. 65 (2): 265–273. doi: 10.1111/j.1365-2265.2006.02562.x . ISSN   1365-2265. PMID   16886971. S2CID   16048818.
  9. ↑ Laufer, Marc R.; Floor, Amy E.; Parsons, Katherine E.; Kuntz, Karen M.; Barbieri, Robert L. (1995). "Hormone Testing in Women with Adult-Onset Amenorrhea". Gynecologic and Obstetric Investigation. 40 (3): 200–203. doi:10.1159/000292335. ISSN   0378-7346. PMID   8529955.
  10. 1 2 3 4 5 6 7 8 9 10 Li, Raymond Hang Wun; Ng, Ernest Hung Yu (2012-12-01). "Management of anovulatory infertility". Best Practice & Research Clinical Obstetrics & Gynaecology. 26 (6): 757–768. doi:10.1016/j.bpobgyn.2012.05.004. hdl: 10722/167096 . ISSN   1521-6934. PMID   22703626.
  11. ↑ Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2008-03-01). "Consensus on infertility treatment related to polycystic ovary syndrome". Human Reproduction. 23 (3): 462–477. doi:10.1093/humrep/dem426. ISSN   0268-1161. PMID   18308833.
  12. ↑ Moran, Lisa J.; Pasquali, Renato; Teede, Helena J.; Hoeger, Kathleen M.; Norman, Robert J. (2009). "Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society". Fertility and Sterility. 92 (6): 1966–1982. doi: 10.1016/j.fertnstert.2008.09.018 . ISSN   0015-0282. PMID   19062007.
  13. ↑ Hamilton-Fairley, D. (2003). "Anovulation". BMJ. 327 (7414): 546–549. doi:10.1136/bmj.327.7414.546. ISSN   0959-8138. PMC   192851 . PMID   12958117.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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. PMID   25164024.
  17. ↑ Sharma, Rakesh; Biedenharn, Kelly R; Fedor, Jennifer M; Agarwal, Ashok (2013). "Lifestyle factors and reproductive health: taking control of your fertility". Reproductive Biology and Endocrinology. 11 (1): 66. doi: 10.1186/1477-7827-11-66 . ISSN   1477-7827. PMC   3717046 . PMID   23870423.
  18. ↑ 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.
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