- Author: Armando E Hernandez-Rey, MD; Chief Editor: Richard Scott Lucidi, MD, FACOG more...
Ovulation is the result of a maturation process that occurs in the hypothalamic-pituitary-ovarian (HPO) axis and is orchestrated by a neuroendocrine cascade terminating in the ovaries. Any alteration results in a failure to release a mature ovum, leading to anovulatory cycles. Anovulation may manifest in a variety of clinical presentations, from luteal insufficiency to oligomenorrhea.
Anovulation is a not a disease but a sign, in much the same way that polycystic ovaries are the manifestation of a much larger disease process.
Education for these patients should focus on an understanding of the underlying disorders to ensure compliance with both medical therapy and lifestyle modifications. For patient education resources, see Women's Health Center, as well as Anorexia Nervosa.
To understand anovulation, one must first understand what occurs during a normal ovulatory cycle. In normal physiology, ovulation is dependent on the presence of a functioning hypothalamic-pituitary-ovarian (HPO) axis. The arcuate nucleus within the hypothalamus is composed of a collection of neurons and, when stimulated, releases GnRH into the portal vessels of the pituitary stalk in a pulsatile fashion. GnRH stimulates receptors in the anterior pituitary gland to produce and secrete both LH and FSH. In women, FSH induces maturation of ovarian follicles and eventual production of estrogen, while LH modulates the secretion of androgens from the ovarian theca cells. Estrogen, in turn, produces negative feedback on the pituitary gland.
As the follicle grows through accumulation of follicular fluid, the cohort of granulosa cells acquire the necessary receptors to respond to LH with increased formation of cyclic adenosine monophosphate (cAMP). During the midcycle, the estrogen levels in the circulation reach a concentration that causes a positive feedback action on LH secretion. This is called the LH surge. Generally speaking, approximately 16-24 hours after the LH peak, ovulation occurs with the extrusion of a mature oocyte from the graafian follicle and the formation of the corpus luteum. These events are the culmination of a well-coordinated interplay between hormones and their appropriate receptors and proteolytic enzymes and prostaglandins acting in concert with one another, all directed by the HPO axis.
The system is so sensitive that even the slightest alteration in any of these factors can disrupt its fluidity and lead to anovulation.
When problems arise at any of the many different levels involved in the normal menstrual cycle, it is sometimes helpful to separate the levels by organ system. The hypothalamus and the anterior pituitary can be considered the neuroendocrine components by virtue of their proximity to each another, while the ovaries are a separate compartment. The third aspect that can be defective is the signaling process that occurs between these 2 areas.
The initial stimulus must come from the hypothalamus in the form of gonadotropin-releasing hormone (GnRH); this decapeptide must be secreted in a pulsatile fashion within a critical range. For example, sexual maturity is not attained until the onset of regular ovulatory cycles, which may take months to years to occur. This maturation process is orchestrated by a neuroendocrine cascade and modified by autocrine and paracrine events in the ovaries, in which GnRH is the principal mediator.
Any alteration in the GnRH pulse generator alters the hormonal milieu necessary for gonadotropin secretion and eventual response at the level of the ovary. Several entities (eg, hyperprolactinemia) are known to cause this type of dysregulation. Increasing levels of prolactin can cause a woman to progress from a deficient luteal phase to overt amenorrhea, usually associated with complete GnRH suppression. More common causes of dysregulation include stress, anxiety, and eating disorders, which are also associated with an inhibition of normal GnRH pulsatility through excessive hypothalamic activity of corticotrophin-releasing hormone and stimulation of beta-endorphins.
How polycystic ovary syndrome (PCOS) is associated with anovulatory cycles has not been completely elucidated. Two associations with this disease entity are theorized to be at least somewhat responsible for its development. The first is the persistent elevation of LH levels in these patients; the second is the apparent arrest of antral follicle development at the 5- to 10-mm stage and consequent failure to enter the preovulatory phase of the cycle. This evidence indicates that the disturbance is mainly a central defect that initiates the cascade of events leading to its onset.
Similarly, any condition, whether primary or secondary, that results in either a persistent elevation or an insufficient attainment of estrogen levels can inhibit ovulation through a disruption of the mechanisms that induce the LH surge. To achieve the corresponding changes within the cycle, estradiol levels must rise and fall appropriately.
Almost all women experience anovulatory cycles at some point in their reproductive lives. Yet, to attempt to determine the frequency of chronic anovulation in the general population is quite difficult because of underreporting. Estimates of chronic anovulation rates range from 6-15% of women during the reproductive years.
Interestingly, an article by Rasgon introduced a certain subset of the population as being at an increased risk for anovulatory disorders, stating that reproductive endocrine disorders, such as PCOS, hypothalamic amenorrhea, premature menopause, and hyperprolactinemia, are reportedly more common in women with epilepsy than in the general female population. The article further elaborates on the frequency of PCOS in patients who endure epilepsy independent of the use of antiepileptic therapy. The risk of developing PCOS during valproate (VPA) treatment seems to be higher in women with epilepsy than in women with bipolar disorders; this might be due to an underlying neuroendocrine dysfunction. Gynecologists must be aware of the possibility that PCOS might be related to VPA use in this population of patients, and the risks and benefits of this treatment should be weighed in the presence of PCOS.
Prognosis is generally favorable with appropriate and timely treatment.
Morbidities associated with chronic anovulation include hyperinsulinemia, insulin resistance, early onset of type 2 diabetes mellitus, dyslipidemia, cardiovascular disease, hypertension, infertility, endometrial hyperplasia, and endometrial cancer.
Complications of anovulation include the following:
Insulin resistance or type 2 diabetes mellitus
Venous thromboembolism secondary to estrogen therapy
Electrolyte derangements (anorexia nervosa)
Arrhythmias (anorexia nervosa)
Women with PCOS who conceive are at increased risk for gestational diabetes, preeclampsia, cesarean delivery, and preterm and post-term delivery. Their newborns are at increased risk of being large for gestational age but are not at increased risk of stillbirth or neonatal death.
In one study, the frequency of anovulation was greater among white women (9 of 63 [14.3%]) than black women (4 of 56 [7.1%]) or Hispanic women (7 of 102 [6.9%]), although these differences were not statistically significant.
Anovulation occurs only in women of reproductive age.
Anovulation is physiologic at the extremes of reproductive age. During menarche, absence of ovulation is due to immaturity of the HPO axis, leading to an uncoordinated secretion of GnRH (pulsatility).
During perimenopause, ovarian factors and a dysregulation of feedback mechanisms are responsible.
When anovulation occurs outside of the perimenarchal or perimenopausal years, extrinsic and intrinsic causes must be excluded.
Warren MP, Vu C. Central causes of hypogonadism--functional and organic. Endocrinol Metab Clin North Am. 2003 Sep. 32(3):593-612. [Medline].
Speroff L, Glass RH, Kase NG. Anovulation and the polycystic ovary syndrome. Clinical Gynecologic Endocrinology and Infertility. Philadelphia, PA: Lippincott Williams & Wilkins; 1999. 487-513.
Spence JE. Anovulation and monophasic cycles. Ann N Y Acad Sci. 1997 Jun 17. 816:173-6. [Medline].
Yen SC, Jaffe RB, Barbieri RL. Chronic anovulation due to CNS-hypothalamic-pituitary dysfunction. Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management. 4th ed. London, England: Elsevier Science; 1999.
Franks S, Mason H, White D, Willis D. Etiology of anovulation in polycystic ovary syndrome. Steroids. 1998 May-Jun. 63(5-6):306-7. [Medline].
Rasgon N. The relationship between polycystic ovary syndrome and antiepileptic drugs: a review of the evidence. J Clin Psychopharmacol. 2004 Jun. 24(3):322-34. [Medline].
Bilo L, Meo R. Polycystic ovary syndrome in women using valproate: a review. Gynecol Endocrinol. 2008 Oct. 24(10):562-70. [Medline].
Haiman CA, Pike MC, Bernstein L, et al. Ethnic differences in ovulatory function in nulliparous women. Br J Cancer. 2002 Feb 1. 86(3):367-71. [Medline].
Laven JS, Imani B, Eijkemans MJ, Fauser BC. New approach to polycystic ovary syndrome and other forms of anovulatory infertility. Obstet Gynecol Surv. 2002 Nov. 57(11):755-67. [Medline].
Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Am J Med. 1995 Jan 16. 98(1A):33S-39S. [Medline].
Guzick DS, Hoeger K. Clinical Updates in Women's Health Care: Polycystic Ovary Syndrome. 2009 Jan.
The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004 Jan. 81(1):19-25. [Medline].
Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009 Feb. 91(2):456-88. [Medline].
Franks S, Robinson S, Willis DS. Nutrition, insulin and polycystic ovary syndrome. Rev Reprod. 1996 Jan. 1(1):47-53. [Medline].
Pritts EA. Treatment of the infertile patient with polycystic ovarian syndrome. Obstet Gynecol Surv. 2002 Sep. 57(9):587-97. [Medline].
Legro R. Polycystic ovary syndrome. Precis, Reproductive Endocrinology: An Update in Obstetrics and Gynecology. 2nd ed. American College of Obstetricians & Gynecologists; 2002. 85-89.
Thatcher S. Diagnosis of polycystic ovary syndrome. Female patient. 2004. 29:33-41.
Futterweit W. Polycystic ovary syndrome: clinical perspectives and management. Obstet Gynecol Surv. 1999 Jun. 54(6):403-13. [Medline].
Bergfeld WF. Hirsutism in women. Effective therapy that is safe for long-term use. Postgrad Med. 2000 Jun. 107(7):93-4, 99-104. [Medline].
Timpatanapong P, Rojanasakul A. Hormonal profiles and prevalence of polycystic ovary syndrome in women with acne. J Dermatol. 1997 Apr. 24(4):223-9. [Medline].
Schorge JO, Schaffer JI. Amenorrhea. Williams Gynecology. McGraw Hill; 2008.
Frisch RE, McArthur JW. Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science. 1974 Sep 13. 185(4155):949-51. [Medline].
Andrico S, Gambera A, Specchia C, et al. Leptin in functional hypothalamic amenorrhoea. Hum Reprod. 2002 Aug. 17(8):2043-8. [Medline].
Klein DA, Walsh BT. Eating disorders. Int Rev Psychiatry. 2003 Aug. 15(3):205-16. [Medline].
Yen SC, Jaffe RB, Barbieri RL. Chronic anovulation caused by peripheral endocrine disorders. Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management. 4th ed. London, England: Elsevier Science; 1999.
Warren MP, Perlroth NE. The effects of intense exercise on the female reproductive system. J Endocrinol. 2001 Jul. 170(1):3-11. [Medline].
Mestman JH. Endocrine diseases in pregnancy. Gabbe S, Neibyl JR, eds. Obstetrics Normal and Problem Pregnancies. New York, NY: Churchill Livingstone; 2002. 4th ed: 1117-8.
Goswami R, Kochupillai N, Crock PA, Jaleel A, Gupta N. Pituitary autoimmunity in patients with Sheehan's syndrome. J Clin Endocrinol Metab. 2002 Sep. 87(9):4137-41. [Medline].
Velduis JD, Weiss J, Mauras N, et al. Appraising endocrine pulse signals at low circulating hormone concentrations: use of regional coefficients of variation in the experimental series to analyze pulsatile luteinizing hormone release. Pediatr Res. 1986 Jul. 20(7):632-7. [Medline].
Bills DC, Meyer FB, Laws ER, et al. A retrospective analysis of pituitary apoplexy. Neurosurgery. 1993 Oct. 33(4):602-8; discussion 608-9. [Medline].
Abe T, Ludecke DK. Transnasal surgery for prolactin-secreting pituitary adenomas in childhood and adolescence. Surg Neurol. 2002 Jun. 57(6):369-78; discussion 378-9. [Medline].
Molitch ME. Disorders of prolactin secretion. Endocrinol Metab Clin North Am. 2001 Sep. 30(3):585-610. [Medline].
Goldman L, Ausiello D. Obesity. Cecil Textbook of Medicine. 22nd ed. 2004. 1346.
Roos N, Kieler H, Sahlin L, Ekman-Ordeberg G, Falconer H, Stephansson O. Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: population based cohort study. BMJ. 2011 Oct 13. 343:d6309. [Medline]. [Full Text].
ACOG Committee on Practice Bulletins, American College of Obstetricians and Gynecologists. ACOG practice bulletin: management of anovulatory bleeding. Int J Gynaecol Obstet. 2001 Mar. 72(3):263-71. [Medline].
Akande EO. Plasma concentration of gonadotrophins, oestrogen and progesterone in hypothyroid women. Br J Obstet Gynaecol. 1975 Jul. 82(7):552-6. [Medline].
Akande EO, Hockaday TD. Plasma concentration of gonadotrophins, oestrogens and progesterone in thyrotoxic women. Br J Obstet Gynaecol. 1975 Jul. 82(7):541-51. [Medline].
Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004 Jun. 89(6):2745-9. [Medline].
Bankowski BJ, Zacur HA. Dopamine agonist therapy for hyperprolactinemia. Clin Obstet Gynecol. 2003 Jun. 46(2):349-62. [Medline].
Barbieri RL. Metformin for the treatment of polycystic ovary syndrome. Obstet Gynecol. 2003 Apr. 101(4):785-93. [Medline].
Baumann EE, Rosenfeld RL. Polycystic ovary syndrome in adolescence. Endocrinologist. 2002. 12:333-48.
Ben-Rafael Z, Orvieto R. Polycystic ovary syndrome: a single gene mutation or an evolving set of symptoms. Curr Opin Obstet Gynecol. 2000 Jun. 12(3):169-73. [Medline].
Boccuzzi G, Angeli A, Bisbocci D, Fonzo D, Giadano GP, Ceresa F. Effect of synthetic luteinizing hormone releasing hormone (LH-RH) on the release of gonadotropins in Cushing's disease. J Clin Endocrinol Metab. 1975 May. 40(5):892-5. [Medline].
Bray GA, York DA. Clinical review 90: Leptin and clinical medicine: a new piece in the puzzle of obesity. J Clin Endocrinol Metab. 1997 Sep. 82(9):2771-6. [Medline].
Brenner PF. Differential diagnosis of abnormal uterine bleeding. Am J Obstet Gynecol. 1996 Sep. 175(3 Pt 2):766-9. [Medline].
Camargo CA. Hypothyroidism and goiter during pregnancy. Brody SA, Ueland K, eds. Endocrine Disorders of Pregnancy. Stamford, Conn: Appleton & Lange; 1989. 1989:165-76.
Campo S. Ovulatory cycles, pregnancy outcome and complications after surgical treatment of polycystic ovary syndrome. Obstet Gynecol Surv. 1998 May. 53(5):297-308. [Medline].
Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab. 1999 Jun. 84(6):1897-9. [Medline].
Clark RA, Mulligan K, Stamenovic E, et al. Frequency of anovulation and early menopause among women enrolled in selected adult AIDS clinical trials group studies. J Infect Dis. 2001 Nov 15. 184(10):1325-7. [Medline].
Cotran RS, Kumar V, Collins T. Anovulation. Robbin's Pathologic Basis of Disease. 6th ed. Elsevier Science; 1999. 1056.
Daniels GH. Thyroid disease and pregnancy: a clinical overview. Endocrinol Pract. 1995. 1:287-301.
del Pozo E, Wyss H, Tollis G, et al. Prolactin and deficient luteal function. Obstet Gynecol. 1979 Mar. 53(3):282-6. [Medline].
Edwards CR, Forsyth IA, Besser GM. Amenorrhoea, galactorrhoea, and primary hypothyroidism with high circulating levels of prolactin. Br Med J. 1971 Aug. 3(772):462-4. [Medline].
Franks S, Gharani N, Waterworth D, et al. Genetics of polycystic ovary syndrome. Mol Cell Endocrinol. 1998 Oct 25. 145(1-2):123-8. [Medline].
Franks S, McCarthy M. Genetics of ovarian disorders: polycystic ovary syndrome. Rev Endocr Metab Disord. 2004 Mar. 5(1):69-76. [Medline].
Frisch RE, Wyshak G, Vincent L. Delayed menarche and amenorrhea in ballet dancers. N Engl J Med. 1980 Jul 3. 303(1):17-9. [Medline].
Goldsmith R, Sturgis S, Lerman J, et al. The menstrual pattern in thyroid disease. J Clin Endocrinol Metab. 1952 Jul. 12(7):846-55. [Medline].
Golovleva LA, Golovlev EL, Ganbarov KhG, Skriabin GK. [Role of cosubstrates in the microbiologic oxidation of xylene isomers by a culture of Pseudomonas aeruginosa]. Mikrobiologiia. 1977 Jan-Feb. 46(1):5-9. [Medline].
Hamilton-Fairley D, Taylor A. Anovulation. BMJ. 2003 Sep 6. 327(7414):546-9. [Medline].
Inamasu J, Hori S, Sekine K, Aikawa N. Pituitary apoplexy without ocular/visual symptoms. Am J Emerg Med. 2001 Jan. 19(1):88-90. [Medline].
Knochenhauer ES, Key TJ, Kahsar-Miller M, et al. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998 Sep. 83(9):3078-82. [Medline].
Malcolm CE, Cumming DC. Does anovulation exist in eumenorrheic women?. Obstet Gynecol. 2003 Aug. 102(2):317-8. [Medline].
Norman RJ. Obesity, polycystic ovary syndrome and anovulation--how are they interrelated?. Curr Opin Obstet Gynecol. 2001 Jun. 13(3):323-7. [Medline].
Norman RJ, Wu R, Stankiewicz MT. 4: Polycystic ovary syndrome. Med J Aust. 2004 Feb 2. 180(3):132-7. [Medline].
Pfeifer SM, Dayal M. Treatment of the adolescent patient with polycystic ovary syndrome. Obstet Gynecol Clin North Am. 2003 Jun. 30(2):337-52. [Medline].
Sabogal JC, Munoz L. Leptin in obstetrics and gynecology: a review. Obstet Gynecol Surv. 2001 Apr. 56(4):225-30. [Medline].
Sakakura M, Takebe K, Nakagawa S. Inhibition of luteinizing hormone secretion induced by synthetic LRH by long-term treatment with glucocorticoids in human subjects. J Clin Endocrinol Metab. 1975 May. 40(5):774-9. [Medline].
Schlechte J, Sherman B, Halmi N, et al. Prolactin-secreting pituitary tumors in amenorrheic women: a comprehensive study. Endocr Rev. 1980 Summer. 1(3):295-308. [Medline].
Serri O, Chik CL, Ur E, Ezzat S. Diagnosis and management of hyperprolactinemia. CMAJ. 2003 Sep 16. 169(6):575-81. [Medline].
Shangold MM. Athletic amenorrhea. Clin Obstet Gynecol. 1985 Sep. 28(3):664-9. [Medline].
Thomas R, Reid RL. Thyroid disease and reproductive dysfunction: a review. Obstet Gynecol. 1987 Nov. 70(5):789-98. [Medline].
Tolino A, Nicotra M, Romano L, et al. Subclinical hypothyroidism and hyperprolactinemia. Acta Eur Fertil. 1991 Sep-Oct. 22(5):275-7. [Medline].
Tsilchorozidou T, Overton C, Conway GS. The pathophysiology of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2004 Jan. 60(1):1-17. [Medline].
Use of exogenous gonadotropins in anovulatory women: a technical bulletin. Fertil Steril. 2008 Nov. 90(5 Suppl):S7-12. [Medline].
Veldhuis JD, Hammond JM. Endocrine function after spontaneous infarction of the human pituitary: report, review, and reappraisal. Endocr Rev. 1980 Winter. 1(1):100-7. [Medline].
Warren MP, Brooks-Gunn J, Fox RP, et al. Persistent osteopenia in ballet dancers with amenorrhea and delayed menarche despite hormone therapy: a longitudinal study. Fertil Steril. 2003 Aug. 80(2):398-404. [Medline].
Warren MP, Goodman LR. Exercise-induced endocrine pathologies. J Endocrinol Invest. 2003 Sep. 26(9):873-8. [Medline].
Warren MP, Vu C. Central causes of hypogonadism--functional and organic. Endocrinol Metab Clin North Am. 2003 Sep. 32(3):593-612. [Medline].
Wilansky DL, Greisman B. Early hypothyroidism in patients with menorrhagia. Am J Obstet Gynecol. 1989 Mar. 160(3):673-7. [Medline].
Wilson JD, Foster DW, Kronenberg HM. Disorders of the ovaries and female reproductive tract. Williams Textbook of Endocrinology. 10th ed. WB Saunders Co; 2003. 751-817.
Winters SJ, Berga SL. Gonadal dysfunction in patients with thyroid disorders. Endocrinologist. 1997. 7:167-73.
Yen SC, Jaffe RB, Barbieri RL. Polycystic ovary syndrome: Hyperandrogenic chronic anovulation. Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management. 4th ed. London, England: Elsevier Science; 1999.
Zakarija M, McKenzie JM. Pregnancy-associated changes in the thyroid-stimulating antibody of Graves' disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab. 1983 Nov. 57(5):1036-40. [Medline].
Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome. Givens J, Haseltine F, Merriman G. The Polycystic Ovary Syndrome. Cambridge, MA: Blackwell Scientific; 1992. 377-384.
Prior JC, Naess M, Langhammer A, Forsmo S. Ovulation prevalence in women with spontaneous normal-length menstrual cycles - a population-based cohort from HUNT3, Norway. PLoS One. 2015. 10(8):e0134473. [Medline].
Schliep KC, Zarek SM, Schisterman EF, et al. Alcohol intake, reproductive hormones, and menstrual cycle function: a prospective cohort study. Am J Clin Nutr. 2015 Oct. 102(4):933-42. [Medline].
Palihawadana TS, Wijesinghe PS, Seneviratne HR. Factors associated with nonresponse to ovulation induction using letrozole among women with World Health Organization group II anovulation. J Hum Reprod Sci. 2015 Apr-Jun. 8(2):75-9. [Medline].