Medical Care
The medical management of anovulation is complex because it entails initiating a multitiered approach to patient care.
First and foremost, the clinician should be well acquainted with the most common etiologies and able to rule them out, specifically those that can pose serious dangers to a patient's immediate health. Fortunately, anovulation usually manifests in a clinical setting geared toward the treatment of chronic diseases and conditions, which provides the precision necessary for an accurate diagnosis. Despite this, patients often have a history of multiple doctor visits because of inadequate or unsuccessful treatment by other physicians secondary to a misdiagnosis. The care of these patients must be tailored to their individual presentations and the specific disease entities responsible for anovulation. A holistic approach, consultation with other specialists, and routine follow-up should be the rule, not the exception.
Acute bleeding secondary to anovulation
Most causes of dysfunctional uterine bleeding respond to either oral or intravenous estrogen. Treatment using the parenteral route can be initiated with estrogen (Premarin) 25 mg IV q4h by accelerating the mitotic activity at the level of the endometrium. If no response is seen after 24 hours, suction dilation and curettage is warranted.
If the bleeding is not as vigorous, high-dose birth control pills (totalling 3 pills/d for 7 d), followed by continuation of oral contraceptives for a minimum of 3 months, has equal efficacy in reestablishing the endometrium.
Because of the menstrual irregularities associated with anovulation, anemia is a concern and must be treated with allogeneic blood transfusion if blood parameters fall below critical levels. Intravenous estrogen (Premarin) or high-dose combined oral contraceptives may be needed to ameliorate or terminate the acute bleeding episode. Dilation and curettage should never be the first-line treatment in this clinical setting; however, in the case of intractable bleeding, it may be the only alternative. Subtotal or total hysterectomy is rarely, if ever, necessary.
Anovulation and amenorrhea
Pregnancy test and hormonal studies measuring thyroid function, prolactin levels, and gonadotropin levels should be obtained. These hormonal assays should be followed by a progestational challenge to evaluate the endometrial lining and the presence of a hypoestrogenic state.
The first possibility is normal levels with a positive withdrawal bleed. This indicates anovulation and unopposed estrogen stimulation. Treatment is focused on providing progesterone support and cyclicity in the form of oral contraceptives or progestin alone, which is paramount in the prevention of endometrial hyperplasia.
If TSH or prolactin levels are elevated, correcting the primary problem is usually enough to attain ovulatory cycles once again.
If gonadotropin levels are low or normal, a diagnosis of hypogonadotropic hypogonadism is assumed and a space-occupying lesion versus hypothalamic suppression due to exercise or weight fluctuations (eg, anorexia nervosa, bulimia) must be ruled out. Treatment again focuses on the cause of the suppression.
If FSH and LH levels are elevated (hypergonadotropic hypogonadism), the problem is usually related to an absence of inhibitory signals that originate from the ovary under normal conditions; therefore, ovarian failure is presumed. Generally, other signs and symptoms of hypoestrogenism, such as vaginal dryness, emotional lability, and hot flushes due to vasomotor spasm, help confirm the diagnosis. If this occurs before age 30 years, a karyotype is necessary to rule out the presence of a Y chromosome or fragile X premutation. Owing to the high rate of malignant germ cell tumors in this setting, a gonadectomy must be performed immediately. Other considerations are certain autoimmune and infectious processes that can destroy ovarian tissue through infiltration of autoimmune complexes.
Surgical Care
Surgical care is usually indicated to resolve the underlying cause for the anovulation, typically when medical therapy has failed.
Surgery is also indicated in rare cases, such as a macroadenoma of the pituitary with unrelenting growth eliciting severe symptoms (eg, headaches, bitemporal hemianopsia, diplopia). In the event of a benign or malignant neoplasm of ovarian or adrenal origin, exploratory laparotomy, resection, and staging are indicated.
Ovarian drilling and ovarian wedge resection are other surgical modalities used in the treatment of anovulation due to PCOS, with a spontaneous ovulation rate of more than 80% after the procedure.
While dilation and curettage is never first-line therapy for acute bleeding, practitioners are sometimes left with no other option. In even rarer cases, hysterectomy may be the only solution to the profound anemia stemming from acute blood loss.
Bariatric surgery has been advocated in the surgical treatment of severe obesity when accompanied by medical complications in which weight loss could be curative. Gastroplasty, vertical banded gastroplasty, gastric banding, and vertical stapling are commonly used but are less effective than the roux-en-Y gastric bypass. Typically patients with a BMI greater than 40 are candidates for surgery, assuming past attempts at medical treatment have failed, although patients with a BMI of 35-40 and underlying life-threatening medical problem may be considered as well. [37]
Consultations
Consider consultations with the following specialists:
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Neurosurgeons - In the presence of a macroadenoma unresponsive to medical management with bromocriptine
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Psychiatrists/psychologists - For patients with body dysmorphic disorder and concomitant anorexia nervosa and bulimia
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Nutritionists - For patients with anorexia nervosa and bulimia
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Endocrinologists - When anovulation is due to adrenal disorders such as Cushing syndrome, Addison disease, overt type 2 diabetes mellitus, panhypopituitarism (ie, Sheehan syndrome), refractory thyroid disease
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Gynecologic oncologists/general surgeons - In the case of either an adnexal mass or adrenal mass of benign or malignant origin
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Reproductive endocrinologists and infertility specialists - When fertility is desired in order to appropriately monitor ovulation induction with either clomiphene citrate or gonadotropins or in the management of PCOS
A systematic review and network meta-analysis by Wang et al reported that letrozole and the combination of clomiphene and metformin had higher pregnancy rates and ovulation rates than clomiphene alone in women with WHO group II anovulation. [38]
Diet and Activity
Diet
When considering a specific diet in the setting of anovulation, the principal focus must be in reference to the endocrinologic and metabolic derangements observed in PCOS. Therefore, a well-structured low-carbohydrate/low-cholesterol regimen is imperative because of the insulin resistance and cardiovascular risks commonly occurring in these patients.
The effectiveness of organized weight loss programs such as Weight Watchers, Curves, or Jenny Craig has been well documented to improve the recidivism rate in overweight patients attempting to lose weight when done in conjunction with counseling and support group initiatives.
Activity
Cardiovascular exercise helps offset the inherent risks associated with PCOS.
Weight-bearing exercise should be recommended for patients with hypoestrogenic states, such as premature ovarian failure, when estrogen replacement is a contraindicated.
Prevention
Long-term health consequences, depending on their etiologic origin, include an increased risk for obesity, diabetes mellitus, heart disease, dyslipidemia, hypertension, endometrial hyperplasia, and infertility, and treatment must be focused on addressing these health concerns in addition to the primary causes (ie, PCOS). Therefore, aggressive preventative health care interventions are warranted, including interventions that lower cardiovascular risk factors through diet, exercise, and judicious use of statin medications when appropriate, as well as endometrial biopsy in the setting of chronic irregular bleeding regardless of age for the diagnosis of endometrial hyperplasia. Assessment must be continued at routine intervals (eg, every 4-6 mo).
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Anovulation. Polycystic ovary. Courtesy of Jairo E. Garcia, MD.
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Anovulation. On the left is an unaffected patient aged 12 years. On the right is the same patient aged 13 years after developing Cushing disease.
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Anovulation. Left adrenal mass discovered incidentally.
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Anovulation. MRI showing a nonenhancing area in the pituitary consistent with a microadenoma in a patient with hyperprolactinemia.
