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Anovulation

Updated : June 3, 2024





Background

Ovulation is the process of maturation that takes place in the HPO (hypothalamic pituitary-ovarian) axis and controlled by a neuroendocrine cascade. Any changes in this process causes anovulatory cycles. This can manifest various clinical presentations like oligomenorrhea or luteal insufficiency.  

Anovulation is a sign of a larger disease process, similar to polycystic ovaries. Education should focus on understanding the underlying disorders to ensure compliance with medical therapy and lifestyle modifications. 

Epidemiology

With an estimate of 6-15%, the prevalence of chronic anovulation in the general population cannot be estimated as they were not reported. A certain subset of women who have hypothalamic amenorrhea, hyperprolactinemia, hypothalamic amenorrhea are more susceptible to this condition. Compared to the general population, female population with epilepsy are more likely to suffer from these disorders. Gynecologists should consider the advantages and disadvantages of this treatment in the presence of PCOS and should be aware of the potential link between the use of VPA and PCOS in these patients. 

Anatomy

Pathophysiology

Anovulation is a natural part of an ovulatory cycle dependent on the proper functioning of Hypothalamic Pituitary Ovarian (HPO) axis. GnRH (gonadotropin releasing hormone) is released by the hypothalamic arcuate nucleus into the pituitary gland to produce both LH and FSH. FSH enhances maturation of ovarian follicles and their eventual production of estrogen whereas LH influences production of androgens from ovarian theca cells. Additionally, estrogen also elicits negative feedback on the pituitary gland. 

During follicle growth, granulosa cell cohorts acquire more receptors to produce more cyclic adenosine monophosphate (cAMP) in response to LH. At midcycle, levels of estrogen reach its threshold concentration causing positive feedback on LH output referred to as LH surge. Ovulation usually occurs within 16-24 hours after peak LH concentration leading to extrusion of mature oocyte from graafian follicle and formation of corpus luteum. 

The system is delicate and even minor shifts in any one of these factors can affect its smoothness resulting into anovulatory cycles. 

Etiology

There are many factors that cause anovulation. Chemical imbalances can occur in case of higher BMI that can cause excessive production of androgens like testosterone. Anxiety or excessive stress can lead to fluctuations in the levels of GnRH, FSH and LH. Intense physical activity can impact the pituitary gland negatively in women due to which required quantity of FSH and LH could not be produced. Disproportion of either prolactin or TSH (thyroid stimulating hormone) can alter ovulation.  

A common disorder, affecting about one among ten women of child-bearing age in the United States, is polycystic ovary syndrome (PCOS). This is believed to be the most common hormonal imbalance in women of reproductive age. For example, polycystic ovarian syndrome makes a woman have more androgens which are male hormones such as testosterone. The ovaries fail to develop because they contain eggs and too much of these androgens will prevent this from happening. Due to its presence tiny painless cysts may develop on the ovaries. It might also be noticed with acne, excessive hair growth (hirsutism) especially around the lips and chin. 

When a girl starts to have her period, it is common for her not to ovulate and have abnormal bleeding. This may also happen around the age of forty-five when women are reaching menopause. These two phases occur due to variation in the hormones. 

Genetics

Prognostic Factors

Numerous health problems can result from chronic anovulation that is usually caused by hormone imbalances, such as hyperinsulinemia, insulin resistance, type 2 diabetes, dyslipidaemia, cardiovascular disease, hypertension, infertility, endometrial hyperplasia as well as endometrial cancer. 

Expectant mothers who have polycystic ovary syndrome suffer from elevated risks of gestational diabetes, caesarean delivery, preterm or post-term delivery, and preeclampsia. 

Clinical History

The patient’s medical history should also document information about infections, pelvic surgery, anatomic anomalies, chromosomal abnormalities, dilatation and curettage, and postsurgical changes in menstrual flow. Moreover, it should contain a detailed history of menses like frequency, regularity, length of cycle and quantity of uterine bleeding, pregnancy losses as well as complications and sexual life. 

Physical Examination

General signs: Voice of the patient and presentation should be evaluated. 

Dermatologic evaluation: Inspect for the presence of facial acne, acanthosis nigricans, stigmata of hepatic disease, and flanks. 

Manifestations of head, eyes, nose, throat, and ears:  

Head: cushingoid facies, facial hair, distribution of hair resembling male pattern baldness 

Eyes: Visual acuity, assessing bitemporal hemianopsia and exophthalmos 

Nose: Anosmia, enlarged nose 

Throat: Turner syndrome (webbing of neck), thyromegaly, carotid bruits 

Ears: disproportionate and enlarged ears 

Manifestations of breast: Evaluation should be done for areola for pigmentation and protuberance, reduced breast size, altered shape of breast, Marshall-Tanner staging, or presence of shield chest 

Abdomen: Evaluate for linea alba, waist/hip ratio, infraumbilical hair and striae. 

Genitourinary: Examine Marshall-Tanner staging, absence of pubic hair, vulvovaginalmucosa, clitoris, male-female escutcheon, mons pubis and vulvar skin. A bimanual examination should be done to remove adnexal/ovarian masses.  

Extremities: Identify anorexia (presence of lanugo) and hirsutism (male hair characteristics) 

Age group

Associated comorbidity

PCOS 

Structural abnormalities of the uterus 

Associated activity

Acuity of presentation

Women with infertility issues may have irregular or absent menstrual cycles. This can indicate problems with ovulation, hormonal imbalances, or conditions such as polycystic ovary syndrome (PCOS). 

Hormonal imbalances can disrupt the normal reproductive processes. Symptoms like excessive facial or body hair growth (hirsutism), acne, or weight gain can indicate hormonal disorders like PCOS. 

Differential Diagnoses

  1. Acromegaly 
  2. Addison disease 
  3. Adnexal tumors 
  4. Alcoholism 
  5. Amenorrhea 
  6. Bipolar disorder 
  7. Contraception 
  8. Anxiety disorders 
  9. Anorexia nervosa 
  10. Adrenal carcinoma 
  11. Depression 
  12. Ectopic pregnancy 
  13. Hypothyroidism 
  14. Hirsutism 
  15. Hydatidiform mole 
  16. Leydig cell tumors 
  17. Luteinizing hormone deficiency 
  18. Menopause 
  19. PCOS (polycystic ovarian syndrome) 
  20. Pituitary microadenomas 
  21. Type I& II diabetes mellitus 
  22. Surgery for craniopharyngiomas 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

The diagnosis and evaluation of anovulation involves a medical history, physical examination, and laboratory tests to assess hormonal imbalances. To address underlying causes, lifestyle modifications such as weight management and stress reduction are recommended. Specific medical treatments include lifestyle modifications, hormonal contraceptives, hormone therapy, and Assisted Reproductive Technologies (ART).

Supportive care includes counselling or support groups to cope with emotional stress and educate about treatment options. Long-term management involves appropriate prenatal care if pregnancy is achieved, and long-term strategies for women not seeking pregnancy. A structured diagnostic and therapeutic pathway can effectively manage anovulation, improving the patient’s quality of life and fertility outcomes. 

 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Diet: Endocrinological and metabolic disturbances in PCOS cause insulin resistance and thus poses risks for cardiovascular diseases; hence there should be a special diet specifically targeting hormonal imbalances when ovulation doesn’t occur normally. 

 

Activity: Cardiovascular exercises help to prevent the risks due to PCOS. When estrogen replacement is indicated, weight bearing exercises should be advised for patients with hypoestrogenic states, such as premature ovarian failure.  

Use of ovulation stimulators

Clomiphene citrate: This drug assists in stimulating the release of pituitary gonadotropins. By reducing the negative feedback of estrogens on hypothalamus, it acts as an antiestrogen. Adding to this, it can also induce ovulation in patients with hypothalamic amenorrhea by effecting the pituitary gland and ovaries. 

Use of thyroid products

Levothyroxine: It is indicated in the correction of normal luteal phase that occurs due to hypothyroidism. 

Use of oral contraceptives

Norethindrone: Administering lower doses of oral contraceptives is an excellent hormone replacement technique. A low dose of ethinyl estradiol or a progestin can be suggested. 

Norgestimate/ Ethinyl estradiol: Administering lower doses of oral contraceptives is an excellent hormone replacement technique. A low dose of ethinyl estradiol or a progestin can be suggested. 

Use of bisphosphonate derivatives

Alendronate: This inhibits bone resorption through acting on osteoclast precursors or osteoclasts. It is used in both women and men for treating osteoporosis. It should be given with large glass of water before food. 

Use of oral antidiabetic agents

Metformin: It lowers the output of hepatic glucose and decreases the absorption of glucose from intestine thereby increasing the uptake of glucose in the peripheral tissues. Metformin is primarily used in patients suffering from type-II diabetes. 

Use of androgens

Finasteride: This drug blocks the conversion of testosterone to dihydrotestosterone which is the most active metabolite of testosterone.  

Spironolactone: This is an antagonist of aldosterone which inhibits the adrenal and ovarian synthesis of androgens. It competes with the binding sites of dihydrotestosterone at hormone receptor sites present on the hair follicles. 

Use of glucocorticoids

Fludrocortisone: This is employed as a partial replacement therapy for adrenocortical insufficiency that is primary and secondary. 

Use of oral antifungal agents

Ketoconazole: This medication inhibits the synthesis of steroids at level of 17-α-hydroxylase/17,20-lyase, which is a crucial enzyme involved in the production of sex steroids. It also inhibits the binding of testosterone to its binding globulin. In few cases, children with advanced bone development might trigger central puberty. In that case, GnRh analogs can be added to the treatment regimen. 

Use of dopamine agonists

Pergolide: This inhibits the secretion of prolactin causing a transient increase in the serum levels of GH and reduced levels of serum LH. It was withdrawn from the US market. 

Use of progestins

Medroxyprogesterone acetate: This is a derivative of progesterone. Anabolic and androgenic effects have been seen. When administered parenterally, it is known to inhibit the production of gonadotropin which further prevents the maturation of follicle and thus ovulation. Orally administered drug leads to the transformation of proliferative endometrium to secretory one. 

Use of estrogens

Conjugated estrogens: These may be useful for the restoration of regular menstrual cycles and may prevent endometrial hyperplasia due to anovulation. 

Use of NSAIDS

Ibuprofen: It is indicated in amenorrhea and reduction of uterine bleeding due to anovuatory cycles. It acts by blocking the formation of prostacyclin which is an antagonist of thromboxane, which acceralates the aggregation of platelets and initiates coagulation. 

Use of aromatase inhibitors

Letrazole: This reduces the amounts of circulating estrogens via inhibition of negative feedback of estrogens of HPA. 

Anastrozole: This is an aromatase inhibitor that significantly reduces the concentrations of serum estradiol via inhibition of the conversion of androstenedione to estrone. 

Use of gonadotropins

Follitropin alfa: This exogenous FSH stimulates the growth of follicles and proliferation of granulosa cells. Human chorionic gonadotropin stimulates the release of follicles. 

Laparoscopic surgery can help diagnose and treat many problems, including infertility in women. The procedure requires small cuts to be made in the abdomen through which a laparoscope is inserted. This is a slender flexible tube fitted with a camera and surgical instruments for viewing as well as performing operation of the reproductive organs. It helps in identifying ovarian cysts, endometriosis, and uterine abnormalities. 

Use of phases of management in treating anovulation

An inclusive medical history consisting of past, family and menstrual history and lifestyle should be considered during the initial assessment. Physical examination entails general health check and observing any signs of hormonal imbalances. Diagnosis process also includes evaluation of hormonal profiles, imaging studies, study of metabolites among others. Treatment may involve lifestyle modifications, weight control, stress management practices and specific therapy targeting on the cause of the problem. Blood tests, ultrasounds or even routine follow-up appointments might be necessary depending on the response of a patient to the treatment. By monitoring side effects and reducing chances of multiple pregnancies, complications can be managed. Supportive care with respect to treating menstrual irregularities, patient education and psychological support play a due role in long-term management. 

 

Medication

 

follitropin alfa and lutropin alfa 

150 units of FSH and 75 units of LH once daily
Adjust the dose if required, by increasing the FSH from 37.5-75 units every 1-2 weeks by an approved preparation of follitropin alfa
Stimulation duration is adjusted in any 1 cycle
1-2 days later, the last dose of FSH/LH, administer human chorionic gonadotropin




1st cycle: Initially, 75 IU subcutaneously each day
Increase the dose after 14 days up to 37.5 IU
Increase the dose after every 7 days as required
Based on the lowest effective dose, the maximum dose is 300IU/day
Maximum treatment of 35 days unless the rise of E2 indicates changes in the development of follicles



 
 

Media Gallary

Anovulation

Updated : June 3, 2024




Ovulation is the process of maturation that takes place in the HPO (hypothalamic pituitary-ovarian) axis and controlled by a neuroendocrine cascade. Any changes in this process causes anovulatory cycles. This can manifest various clinical presentations like oligomenorrhea or luteal insufficiency.  

Anovulation is a sign of a larger disease process, similar to polycystic ovaries. Education should focus on understanding the underlying disorders to ensure compliance with medical therapy and lifestyle modifications. 

With an estimate of 6-15%, the prevalence of chronic anovulation in the general population cannot be estimated as they were not reported. A certain subset of women who have hypothalamic amenorrhea, hyperprolactinemia, hypothalamic amenorrhea are more susceptible to this condition. Compared to the general population, female population with epilepsy are more likely to suffer from these disorders. Gynecologists should consider the advantages and disadvantages of this treatment in the presence of PCOS and should be aware of the potential link between the use of VPA and PCOS in these patients. 

Anovulation is a natural part of an ovulatory cycle dependent on the proper functioning of Hypothalamic Pituitary Ovarian (HPO) axis. GnRH (gonadotropin releasing hormone) is released by the hypothalamic arcuate nucleus into the pituitary gland to produce both LH and FSH. FSH enhances maturation of ovarian follicles and their eventual production of estrogen whereas LH influences production of androgens from ovarian theca cells. Additionally, estrogen also elicits negative feedback on the pituitary gland. 

During follicle growth, granulosa cell cohorts acquire more receptors to produce more cyclic adenosine monophosphate (cAMP) in response to LH. At midcycle, levels of estrogen reach its threshold concentration causing positive feedback on LH output referred to as LH surge. Ovulation usually occurs within 16-24 hours after peak LH concentration leading to extrusion of mature oocyte from graafian follicle and formation of corpus luteum. 

The system is delicate and even minor shifts in any one of these factors can affect its smoothness resulting into anovulatory cycles. 

There are many factors that cause anovulation. Chemical imbalances can occur in case of higher BMI that can cause excessive production of androgens like testosterone. Anxiety or excessive stress can lead to fluctuations in the levels of GnRH, FSH and LH. Intense physical activity can impact the pituitary gland negatively in women due to which required quantity of FSH and LH could not be produced. Disproportion of either prolactin or TSH (thyroid stimulating hormone) can alter ovulation.  

A common disorder, affecting about one among ten women of child-bearing age in the United States, is polycystic ovary syndrome (PCOS). This is believed to be the most common hormonal imbalance in women of reproductive age. For example, polycystic ovarian syndrome makes a woman have more androgens which are male hormones such as testosterone. The ovaries fail to develop because they contain eggs and too much of these androgens will prevent this from happening. Due to its presence tiny painless cysts may develop on the ovaries. It might also be noticed with acne, excessive hair growth (hirsutism) especially around the lips and chin. 

When a girl starts to have her period, it is common for her not to ovulate and have abnormal bleeding. This may also happen around the age of forty-five when women are reaching menopause. These two phases occur due to variation in the hormones. 

Numerous health problems can result from chronic anovulation that is usually caused by hormone imbalances, such as hyperinsulinemia, insulin resistance, type 2 diabetes, dyslipidaemia, cardiovascular disease, hypertension, infertility, endometrial hyperplasia as well as endometrial cancer. 

Expectant mothers who have polycystic ovary syndrome suffer from elevated risks of gestational diabetes, caesarean delivery, preterm or post-term delivery, and preeclampsia. 

The patient’s medical history should also document information about infections, pelvic surgery, anatomic anomalies, chromosomal abnormalities, dilatation and curettage, and postsurgical changes in menstrual flow. Moreover, it should contain a detailed history of menses like frequency, regularity, length of cycle and quantity of uterine bleeding, pregnancy losses as well as complications and sexual life. 

General signs: Voice of the patient and presentation should be evaluated. 

Dermatologic evaluation: Inspect for the presence of facial acne, acanthosis nigricans, stigmata of hepatic disease, and flanks. 

Manifestations of head, eyes, nose, throat, and ears:  

Head: cushingoid facies, facial hair, distribution of hair resembling male pattern baldness 

Eyes: Visual acuity, assessing bitemporal hemianopsia and exophthalmos 

Nose: Anosmia, enlarged nose 

Throat: Turner syndrome (webbing of neck), thyromegaly, carotid bruits 

Ears: disproportionate and enlarged ears 

Manifestations of breast: Evaluation should be done for areola for pigmentation and protuberance, reduced breast size, altered shape of breast, Marshall-Tanner staging, or presence of shield chest 

Abdomen: Evaluate for linea alba, waist/hip ratio, infraumbilical hair and striae. 

Genitourinary: Examine Marshall-Tanner staging, absence of pubic hair, vulvovaginalmucosa, clitoris, male-female escutcheon, mons pubis and vulvar skin. A bimanual examination should be done to remove adnexal/ovarian masses.  

Extremities: Identify anorexia (presence of lanugo) and hirsutism (male hair characteristics) 

PCOS 

Structural abnormalities of the uterus 

Women with infertility issues may have irregular or absent menstrual cycles. This can indicate problems with ovulation, hormonal imbalances, or conditions such as polycystic ovary syndrome (PCOS). 

Hormonal imbalances can disrupt the normal reproductive processes. Symptoms like excessive facial or body hair growth (hirsutism), acne, or weight gain can indicate hormonal disorders like PCOS. 

  1. Acromegaly 
  2. Addison disease 
  3. Adnexal tumors 
  4. Alcoholism 
  5. Amenorrhea 
  6. Bipolar disorder 
  7. Contraception 
  8. Anxiety disorders 
  9. Anorexia nervosa 
  10. Adrenal carcinoma 
  11. Depression 
  12. Ectopic pregnancy 
  13. Hypothyroidism 
  14. Hirsutism 
  15. Hydatidiform mole 
  16. Leydig cell tumors 
  17. Luteinizing hormone deficiency 
  18. Menopause 
  19. PCOS (polycystic ovarian syndrome) 
  20. Pituitary microadenomas 
  21. Type I& II diabetes mellitus 
  22. Surgery for craniopharyngiomas 

The diagnosis and evaluation of anovulation involves a medical history, physical examination, and laboratory tests to assess hormonal imbalances. To address underlying causes, lifestyle modifications such as weight management and stress reduction are recommended. Specific medical treatments include lifestyle modifications, hormonal contraceptives, hormone therapy, and Assisted Reproductive Technologies (ART).

Supportive care includes counselling or support groups to cope with emotional stress and educate about treatment options. Long-term management involves appropriate prenatal care if pregnancy is achieved, and long-term strategies for women not seeking pregnancy. A structured diagnostic and therapeutic pathway can effectively manage anovulation, improving the patient’s quality of life and fertility outcomes. 

 

Diet: Endocrinological and metabolic disturbances in PCOS cause insulin resistance and thus poses risks for cardiovascular diseases; hence there should be a special diet specifically targeting hormonal imbalances when ovulation doesn’t occur normally. 

 

Activity: Cardiovascular exercises help to prevent the risks due to PCOS. When estrogen replacement is indicated, weight bearing exercises should be advised for patients with hypoestrogenic states, such as premature ovarian failure.  

Clomiphene citrate: This drug assists in stimulating the release of pituitary gonadotropins. By reducing the negative feedback of estrogens on hypothalamus, it acts as an antiestrogen. Adding to this, it can also induce ovulation in patients with hypothalamic amenorrhea by effecting the pituitary gland and ovaries. 

Levothyroxine: It is indicated in the correction of normal luteal phase that occurs due to hypothyroidism. 

Norethindrone: Administering lower doses of oral contraceptives is an excellent hormone replacement technique. A low dose of ethinyl estradiol or a progestin can be suggested. 

Norgestimate/ Ethinyl estradiol: Administering lower doses of oral contraceptives is an excellent hormone replacement technique. A low dose of ethinyl estradiol or a progestin can be suggested. 

Alendronate: This inhibits bone resorption through acting on osteoclast precursors or osteoclasts. It is used in both women and men for treating osteoporosis. It should be given with large glass of water before food. 

Metformin: It lowers the output of hepatic glucose and decreases the absorption of glucose from intestine thereby increasing the uptake of glucose in the peripheral tissues. Metformin is primarily used in patients suffering from type-II diabetes. 

Finasteride: This drug blocks the conversion of testosterone to dihydrotestosterone which is the most active metabolite of testosterone.  

Spironolactone: This is an antagonist of aldosterone which inhibits the adrenal and ovarian synthesis of androgens. It competes with the binding sites of dihydrotestosterone at hormone receptor sites present on the hair follicles. 

Fludrocortisone: This is employed as a partial replacement therapy for adrenocortical insufficiency that is primary and secondary. 

Ketoconazole: This medication inhibits the synthesis of steroids at level of 17-α-hydroxylase/17,20-lyase, which is a crucial enzyme involved in the production of sex steroids. It also inhibits the binding of testosterone to its binding globulin. In few cases, children with advanced bone development might trigger central puberty. In that case, GnRh analogs can be added to the treatment regimen. 

Pergolide: This inhibits the secretion of prolactin causing a transient increase in the serum levels of GH and reduced levels of serum LH. It was withdrawn from the US market.