Anovulation Clinical Presentation
- Author: Armando E Hernandez-Rey, MD; Chief Editor: Richard Scott Lucidi, MD, FACOG more...
Past medical and surgical history
Obtain information about infections, history of pelvic surgery, anatomic anomalies, previous diagnosis of chromosomal abnormalities, past history of dilatation and curettage (history of postsurgical changes in menstrual flow, including amenorrhea and Asherman syndrome).
Past family history
Does/did the mother and/or sisters have similar symptoms?
History of pubertal development
When was the onset of menarche, pubarche, and growth spurt?
Detailed history of the menses
What is the current frequency, regularity or irregularity, length, and quantity of uterine bleeding?
Past reproductive history
Obtain information about pregnancy losses; antepartum, intrapartum, and postpartum complications, including dilatation and curettage, because of retained products of conception after an early pregnancy loss and after a normal vaginal delivery.
Past and current sexual activity
Obtain information about the number of partners, as well as a history of sexually transmitted diseases, painful intercourse, and vaginal symptoms (eg, burning, postcoital bleeding).
What are the methods of contraception and duration of use, such as type of oral contraceptives and intrauterine devices (IUDs), including progestin-IUDs?
Has there been any recent weight gain or weight loss?
Obtain information about past and present medication use.
History of previous malignancies
Obtain information about previous malignancies (eg, craniopharyngioma, leukemia, Hodgkin disease) and treatments received (eg, radiation, alkylating chemotherapeutic agents).
Review of symptoms
Has the patient experienced any of the following:
Changes in hair distribution or appearance
Deepening of voice
Breast secretions (unilateral, bilateral)
Obtain and document the patient's vital signs.
Evaluate the patient's voice, affect, and presentation (eg, disheveled, well-groomed).
Does the patient have facial acne (cystic), acanthosis nigricans (velvety dark patches usually found on the lateral aspects of the neck, axillae, and inner aspects of the thighs), stigmata of hepatic disease (telangiectasia, caput medusae), and/or violaceous striae usually in the flanks (Cushing syndrome)?
Head, eyes, ears, nose, and throat
Assess the following:
Head - Hair distribution (male pattern baldness), facial hair, cushingoid facies
Eyes - Exophthalmos, visual acuity and visual fields (ruling out bitemporal hemianopsia)
Ears - Enlarged, disproportionate ( acromegaly)
Nose - Enlarged (disproportionate to rest of face [acromegaly]), anosmia (scent of orange peels [ Kallmann syndrome])
Throat - Webbing of neck ( Turner syndrome [ie, remnants of cystic hygroma]), carotid bruits, thyromegaly
Evaluate the patient's Marshall-Tanner staging, areola (protuberance, pigmentation), secretions, shape of breasts (cylindrical as in exogenous estrogen exposure), decrease in breast size (androgen exposure), and/or presence of a shield chest (Turner syndrome).
Are murmurs present?
Assess for a linea alba, infraumbilical hair distribution, waist/hip ratio, and striae (as above).
Assess the mons pubis, Marshall-Tanner staging, male-female escutcheon, absence of pubic hair (androgen insensitivity syndrome), vulvar skin (hypoestrogenized), vulvovaginal mucosa (hypoestrogenized), and clitoris (clitoral index, >35 mm2). Perform a bimanual examination to exclude ovarian/adnexal masses, age-appropriateness of genitalia
Volumes have been written on the different clinical entities associated with anovulation. Based on serum gonadotropins and ovarian hormones, clinicians are usually able to discern whether the ovulatory dysfunction is of central or ovarian origin. In the presence of PCOS, hormone levels are usually within the reference range, but they are accompanied by a wide array of clinical manifestations that may signal the presence of this disorder. The following describes the most important causes of anovulation and elaborates on their clinical and biochemical manifestations:
First described in 1935 by Stein and Leventhal, PCOS is the most common endocrinopathy in women of reproductive age, with a prevalence of approximately 6.5%. Its cardinal features are hyperandrogenism and polycystic ovaries. Clinically, PCOS is characterized by menstrual irregularities, hyperandrogenism, hyperinsulinemia, and long-term metabolic disturbances, such as diabetes mellitus, cardiovascular disease, and dyslipidemias. Risk factors include history of premature adrenarche, family history of PCOS, and history of weight gain during the perimenarchal time.
During the Rotterdam Conference of 2003, a revision of the diagnostic criteria the US National Institutes of Health conference initially proposed in 1990 was made to include the findings of polycystic ovaries. In 2006, the Androgen Excess Society has proposed a new set of criteria for the diagnosis of PCOS where the patient must demonstrate clinical or biological signs of hyperandrogenism plus additional criteria.
2003 consensus statement on PCOS
Any 2 of 3 of the following criteria must be present:
Clinical and/or biochemical signs of hyperandrogenism and exclusion of other etiologies (eg, congenital adrenal hyperplasia [CAH], androgen-secreting tumors, Cushing syndrome)
Oligo-ovulation or anovulation
Polycystic ovaries - Presence of 12 or more follicles in each ovary measuring 2-9 mm in diameter and/or increased ovarian volume greater than 10 mL  (See the image below.)
2006 Androgen Excess Society 
Both of the following criteria must be present:
Clinical and/or biochemical signs of hyperandrogenism and exclusion of other etiologies
Ovulatory dysfunction as demonstrated by oligo-ovulation/anovulation or polycystic appearing ovaries
Because of the disparity between follicular growth and steroidogenesis, Franks et al have proposed that a premature activation of LH-induced mitotic arrest, which occurs normally at the onset of the midcycle LH surge, is responsible for the ovulatory dysfunction noted in patients with PCOS. Therefore, a combination of elevated LH levels with enhanced LH action may be responsible not only for the arrested growth of the follicles but also the increased production of estradiol.[14, 5]
Franks et al further hypothesize that these mechanisms may be intimately related to overproduction of cAMP at the level of the granulosa cell, whereby follicular arrest occurs simultaneously with excess androgen production.
Hyperinsulinemia and insulin resistance
Insulin resistance, independent of obesity, has also been described as being pathognomonic of PCOS. Impaired glucose tolerance has a prevalence of 30% and undiagnosed type 2 diabetes mellitus has a prevalence of 8-10% in women with PCOS. Mechanisms have been proposed to account for the excess insulin production by the pancreas: (1) decreased insulin binding, (2) decreased insulin receptor numbers (down-regulation), and (3) postreceptor failures due to serine phosphorylation and eventual increase in pancreatic beta-cell stimulation.
Regardless of the cause, insulin resistance is predominantly seen peripherally, at the level of skeletal muscle, where 85-90% of circulating insulin is used. The compensatory hyperinsulinemia that occurs contributes to androgen excess by directly stimulating androgen production in the adrenal cortex and through a direct effect on granulosa cells and a simultaneous decrease of sex hormone–binding globulin (SHBG) in the ovaries.
Increased insulin levels can lead to hyperplasia of the basal layer of the epidermis, resulting in velvety hyperpigmented areas of skin usually located on the back of the neck, the axilla, under the breasts, and inner thighs. These lesions are known as acanthosis nigricans.
A centripetal, or apple-shaped, distribution of adipose tissue (waist-hip ratio, >0.88) is associated with a greater risk for hypertension, diabetes, and dyslipidemia.
Although many of the metabolic abnormalities can be alleviated with weight loss, they are still present. PCOS is neither caused by obesity nor cured by weight reduction.
Hirsutism and acne
Hirsutism is the excessive growth of terminal hair, usually in a midline distribution or male-type pattern. The condition is characterized by a response of the pilosebaceous unit to androgens, causing a transformation of vellus to terminal hair in androgen-dependent areas. Hirsutism is classified into the following groups: (1) idiopathic, (2) drug-induced, and (3) due to androgen excess. Most cases of hirsutism result from a combination of mildly increased androgen production and increased skin sensitivity to androgens. Cases that are not androgen-dependent (eg, those caused by medications or familial hypertrichosis) are best diagnosed by physical examination.
Approximately 95% of women with androgen-dependent hirsutism have both adrenal and ovarian causes. The most common cause of hirsutism is PCOS. Additionally, different cultures and races tend to have or display hair in different amounts and locations. These patients are generally classified into the first group in the presence of normal levels of circulating androgens.
If excess androgens are the primary cause of the hirsutism, androgen receptors are found in the anagen (active) phase in the follicles' dermal papillae and associated sebaceous glands, where stimulation is provided by the more potent androgens testosterone and dihydrotestosterone. In excessive amounts, they cause hirsutism, except on the scalp, where androgenic alopecia is induced.
A clinical tool that offers an objective assessment of the hirsute patient is the modified Ferriman-Gallwey scale proposed by Hatch and coworkers. It takes into account 9 of the 11 sites originally described, each receiving a score of 0-4 (maximum). A score of 8 or more is considered significant.
The presence of hirsutism in conjunction with other signs of virilization should alert the physician to the possibility of androgen-producing tumors of adrenal or ovarian origin.
Acne vulgaris, usually seen in adolescence, is directly associated with the level of circulating androgen concentration. In a study of postpubertal women with the chief complaint of acne, PCOS was diagnosed in 37% of participants.
Chronic anovulation with estrogen present can occur in a variety of endocrine disorders. It can occur in women with PCOS and other functional abnormalities, including those with Cushing syndrome, hyperthyroidism, hypothyroidism, late-onset adrenal hyperplasia resulting from 21-hydroxylase deficiency, 11-alpha-hydroxylase deficiency, or 3-beta-hydroxysteroid dehydrogenase deficiency.
Chronic anovulation may also involve tumors of the ovary, including granulosa-theca cell tumors, Brenner tumors, cystic teratomas, mucinous cystadenomas, and Krukenberg tumors. These tumors secrete excess estrogen or androgens that undergo aromatization in extraglandular sites.
Premature ovarian failure
Premature ovarian failure (POF), also known as hypergonadotropic hypogonadism, occurs when oocytes and the surrounding cells are lost prior to 40 years of age. Because the ovaries do not respond to FSH and LH (hypogonadism), there is no negative feedback creating a hypergonadotropic state. POF is diagnosed with 2 serum FSH levels greater than 40 mIU/mL at least 1 month apart. The incidence of POF has been estimated by Coulam in 1986 as 1 in 1,000 women younger than 30 years, and 1 in 100 women younger than 40 years. Gonadal dysgenesis is the most frequent cause of POF, two thirds of which are a result of a deletion on an X chromosome. Although a normal complement of germ cells is present in the early fetal ovary, oocytes undergo accelerated atresia, and the ovary is replaced by a fibrous streak.
Cushing syndrome is characterized by hypercortisolism. Its clinical manifestations encompass a spectrum of symptoms, the severity of which is often influenced by the presence or absence of androgen excess. Progressive obesity and abnormal waist/hip ratio are not uncommon, although the limbs are often spared. Frequently, patients experience proximal muscle weakness and cannot rise from a sitting position. Patients can also be hypertensive as a result of mineralocorticoid excess.
Normally, cortisol-releasing hormone and hypothalamic factors are released into the hypophyseal portal blood and carried to the anterior pituitary, where they stimulate the release of adrenocorticotropic hormone (ACTH). In Cushing disease, the increased plasma ACTH concentrations stimulate increased adrenocorticoid secretion, thus inhibiting hypothalamic corticotropin-releasing hormone (CRH) secretion and other factors from the pituitary. This aberration in the cycle, as well as changes in secretory patterns, are thought to influence the mechanisms involved in ovulatory function. Although the exact mechanisms have not been elucidated, it is believed that hypercortisolism and adrenal hyperandrogenism suppress gonadotropin secretion with impaired LH response to GnRH.
Adrenal insufficiency can be due to a variety of causes, including deficient hypothalamic secretion of CRH, deficient pituitary secretion of ACTH, or destruction of the adrenal cortex (Addison disease, primary adrenal insufficiency).
Adrenal androgen deficiency results in loss of axillary and pubic hair in women and decreased libido. Women with autoimmune adrenal insufficiency are at increased risk of premature ovarian failure and anovulation.
Congenital adrenal hyperplasia
CAH encompasses a group of autosomal recessive disorders caused by an inherited deficiency of enzymes involved in cortisol synthesis in the adrenal cortex.
These disorders, listed in decreasing order of frequency, include a deficiency of 21-hydroxylase, 11-alpha-hydroxylase, and 3-beta-hydroxysteroid dehydrogenase. Hyperandrogenism induces a disruption of the HPO axis and consequently leads to menstrual irregularities or anovulatory cycles.
Some women experience oligomenorrhea. Increased thyroid hormone levels raise SHBG production and therefore serum levels, reflecting increased tissue response to these hormones. Total estrogen and testosterone circulating levels are also increased.
The levels of active or free fractions of these sex steroids are often reduced. Treatment of hyperthyroidism results in regular ovulatory menstrual cycles and fertility. Mid luteal phase progesterone levels in thyrotoxic women improve after treatment.
Women with hypothyroidism often experience the spectrum of menorrhagia and metrorrhagia. Patients with hypothyroidism have reduced levels of SHBG and decreased levels of circulating estrogens and testosterone. Follicle-stimulating hormone (FSH) and LH levels are also reduced. Hypothyroidism can cause aberrations in coagulation. It is believed that a hypothyroid state leads to decreased levels of factors VII, VIII, IX, and XI. Hypothyroidism is the most common endocrinologic condition associated with anovulation.
In addition, hypothyroidism alters steroid metabolism and clearance, which may lead to endometrial dysfunction. This evidence supports the fact that menorrhagia is a symptom of hypothyroidism. These symptoms are easily treated with thyroid hormone replacement. Hypothyroidism leads to increased levels of thyroid-releasing hormone and therefore increased levels of thyroid-stimulating hormone (TSH [ie, thyrotropin]) and prolactin. Hyperprolactinemia from long-standing primary hypothyroidism may be responsible for varying degrees of ovulatory dysfunction.
Prolactin excess manifests clinically as infertility, oligomenorrhea, and amenorrhea. The mechanism seems to involve the inhibition of pituitary gonadotropins via suppression of GnRH pulsatility. As a result of this inhibition, serum gonadotropin levels are significantly decreased, causing secondary hypogonadism. Mild hyperprolactinemia may cause infertility, even in the presence of a regular menstrual cycle, while elevated levels of prolactin may cause galactorrhea.
Patients with hyperprolactinemia must always have a complete history and physical examination to rule out easily correctable causes of hyperprolactinemia. Some of these causes include medication usage (eg, exogenous estrogens, neuroleptics, antidepressants, some antipsychotic medications). MRI should be obtained to rule out a mass lesion in the hypothalamic-pituitary region (see image below). Usually, imaging is not warranted unless levels surpass 100 ng/mL after a negative pregnancy test result. Normalization of prolactin levels through the adjustment of current medications or addition of bromocriptine restores ovulation and fertility.
Eating disorders and aggressive exercise habits
Anorexia is defined as a serious, usually chronic psychiatric disorder of an indolent nature that can be life-threatening if unrecognized. The condition is characterized by a patient's inability to maintain a weight of at least 85% of her ideal body weight. Other essential features of the disorder include an intense fear of gaining weight, a distorted body image (body dysmorphic syndrome), and amenorrhea.
Below-average body weight is not in itself enough to cause amenorrhea; the numerous mechanisms intimately related to profound weight loss are also factors. Frisch and McArthur have suggested that a minimum of 17% body fat is required for the initiation of menses, and at least 22% body fat is necessary for menstrual cyclicity. Leptin, a serum hormone secreted by adipose tissues in proportion to total body lipid stores, has recently received much attention for its role in the pathogenesis of weight and menstrual control in these patients.
A diurnal secretion pattern has been established in women of reproductive age who have a normal body mass index (BMI). Athletes with exercise-induced amenorrhea exhibit leptin levels similar to those of prepubertal girls and consequently lose the diurnal release pattern. Andrico et al demonstrated that leptin levels are significantly lower in patients with functional hypothalamic amenorrhea compared with those of controls who were matched for both age and weight. These investigators suggest that energy balance can interfere with the ratios of body weight to leptin and BMI to leptin in functional hypothalamic amenorrhea.
The consequences of exercise-induced amenorrhea are similar to those of estrogen deficiency. These patients are at an increased risk of osteopenia and, eventually, osteoporosis if not treated expeditiously. Vaginal atrophy and infertility issues are generally the rule. A multidisciplinary approach is therefore necessary when treating these patients in order to address underlying issues and physical manifestations.
Amenorrhea is a consequence of multiple alterations in female hormonal pathways. Anorexic women show a 24-hour pattern of FSH and LH similar to that observed in prepubescent children. They may also exhibit altered ACTH levels and characteristically low triiodothyronine (T3) levels.
The mechanisms involved in amenorrhea caused by excessive exercise or anorexia nervosa are not well understood. However, links seem to exist among malnutrition, chronic disease, and hormonal alterations. Excessive levels of endogenous opioids, with a concomitant increase in CRH secretion, inhibit GnRH release as well. Patients can expect an increased risk of infertility, vaginal and breast atrophy, and osteopenia.
Bulimia nervosa is a another eating disorder in which a female consumes large amounts of food followed by inappropriate behavior to avoid weight gain, most commonly by inducing vomiting, otherwise known as the binge-and-purge cycle. Fluctuations or extreme weight loss are not common. However, these patients usually experience menstrual irregularities or anovulatory cycles. Commonly, they have halitosis and dental caries. They may also exhibit strange behavior when eating in a group setting. Bulimic patients usually prefer to eat during times that do not coincide with those of other members of the household.
The pathophysiology of anovulation in bulimic women is very similar to that of anorexic women, although the neuroendocrine disturbances are significantly milder than in anorexia. LH levels are reduced because of a blunting of the GnRH pulse generator, which leads to the menstrual disturbances commonly observed. Thyroid function is altered, as well as glucose tolerance, with accompanying hypercortisolemia.
Hypothalamic and pituitary causes
The presence of GnRH is essential; studies have shown that the administration of a GnRH antagonist to women at midcycle prevents the LH surge. The physiologic capabilities of the hypothalamic GnRH neurons and pituitary gland are subject to disruption by several pathologic entities, including tumors, trauma, and irradiation.
Hypothalamic causes include tumors, trauma, and irradiation
Note the following:
Hypothalamic tumors can produce space-occupying lesions that are frequently suprasellar. These tumors can cause abnormally low levels of circulating pituitary hormone by compression of the hypothalamus or pituitary stalk, essentially causing delayed puberty, anovulation, and amenorrhea. Craniopharyngioma is an epithelial cell tumor of nonpituitary origin that accounts for approximately 3% of intracranial neoplasms; it is the most common neoplasm associated with delayed puberty. Craniopharyngiomas arise from remnants of Rathke pouch epithelium and result from incomplete closure of the hypophyseal or craniopharyngeal duct.
The clinical features are dependent upon the rate of growth of the tumor and can include visual impairment (ie, bitemporal hemianopsia [70%] due to compression of the optic chiasm), pituitary-adrenal dysfunction (50%), hypothyroidism (25%), somnolence (20%), and diabetes insipidus (10%). [4, 25] The evaluation of craniopharyngioma includes the use of CT scanning and MRI. Most lesions are evidenced by enlargement of the pituitary fossa, and suprasellar extension and calcifications are common. Treatment involves surgical extirpation followed by intensive postoperative radiation.
A major complication is both hypothalamic and pituitary deficiency despite a conservative surgical approach. After surgical management with tumor irradiation, the 10-year survival rate for people with craniopharyngioma is 70-80%. 
An endodermal sinus tumor is a highly malignant germ cell tumor of the hypothalamus commonly observed in the first and second decades of life. Believed to be derived from antecedents of the yolk sac, it produces alpha-fetoprotein. It is a highly vascular neoplasm that metastasizes early to various regions of the CNS.
Hand-Schüller-Christian disease (histiocytosis X) is a rare destructive lesion in children that causes delayed puberty, growth retardation, and diabetes insipidus. These tumors are composed of mononuclear phagocytic cells (histiocytes) that infiltrate and destroy hypothalamic tissue. Clinical features include visual disturbances, hyperprolactinemia, hypopituitarism, anovulation, obesity, and growth retardation. The first presenting symptom is usually growth retardation in a child. Diagnosis is established by biopsy of the lesion, and subsequent treatment is with radiation therapy and growth hormone (GH) replacement.
Head injury can cause hypothalamic damage and result in secondary hypopituitarism (ie, a lack of appropriate hypothalamic-releasing factors). The presence of hyperprolactinemia resulting from the traumatic disruption of dopamine inhibition provides evidence of the location of the lesion and helps the clinician differentiate hypothalamic damage from panhypopituitarism in the presence of normal or even low levels of other pituitary hormones.
Motor vehicle accidents are thought to cause transection of the hypothalamic-pituitary stalk during forward motion of the head. Transection usually manifests first as diabetes insipidus and then as secondary hypopituitarism and hyperprolactinemia.
The hypothalamus is radiosensitive; therefore, external irradiation can cause damage to the hypothalamus and impair its function. In contrast, pituitary cells are relatively radioresistant. Therefore, hypopituitarism that occurs after the administration of external irradiation to the brain typically results from hypothalamic damage.
Similarly, irradiation of the head and neck for treatment of nasopharyngeal cancer frequently results in hypopituitarism as early as 1 year after therapy. 
Pituitary causes include trauma and irradiation.
Note the following:
The most common cause of pituitary trauma is iatrogenic, occurring during neurosurgery. Other causes include birth trauma, intracranial hemorrhage, fetal asphyxia, and breech delivery, all of which may lead to direct pituitary damage. A sella turcica fracture or pituitary stalk transsection can cause panhypopituitarism and/or diabetes insipidus (if the posterior pituitary is involved). The degree of hypopituitarism varies and typically manifests within a year after trauma has occurred. Many patients do not experience signs of posttraumatic pituitary failure for several decades.
Irradiation can cause a significant degree of reproductive dysfunction and anovulation, usually due to hypothalamic damage because pituitary cells exhibit little radiosensitivity. Anticancer treatments are also associated with psychologic stress and weight loss, which can magnify the degree of menstrual dysfunction. The effects of cranial irradiation are dose related, and 70% of women undergoing cranial irradiation experience menstrual irregularities. 
Nonneoplastic causes of hypopituitarism include empty sella syndrome, Sheehan syndrome, pituitary apoplexy, and pituitary adenomas.
Note the following:
Empty sella syndrome is a benign cause of hyperprolactinemia in 4-16% of women who present with amenorrhea and galactorrhea.  It is characterized by an abnormal relationship between the sella turcica and the sellar diaphragm that results in the herniation of the subarachnoid space into the pituitary fossa. A flattening of the pituitary gland and concomitant separation of the gland from the hypothalamus occurs, which can result in the inhibition of GnRH and subsequent anovulation. The degree of flattening of the pituitary also plays a role in the anovulation. Typically, if 90% of the gland is compressed, pituitary failure ensues.
The characteristic changes in the relationships between the sellar contents and the suprasellar arachnoid space can be congenital (primary empty sella syndrome) or can result from surgery, radiation, or spontaneous infarction of pituitary adenomas (secondary empty sella syndrome). The diagnosis of empty sella syndrome is usually incidental in patients being evaluated for symptoms of headache and/or an unusual presentation of rhinorrhea. The preferred radiologic imaging modality, MRI, reveals a symmetrically enlarged sella turcica from cerebrospinal fluid (CSF) and demonstrable pituitary flattening with lateral stalk deviation, which can make the fossa initially appear empty.
CT-guided intrathecal injection of contrast (metrizamide) can be also be used to demonstrate abnormalities in intracranial CSF distribution. The resultant endocrine abnormalities are varied. Because empty sella syndrome is associated with compression of the infundibular stalk, the disruption of dopamine reaching the pituitary leads to concomitant hyperprolactinemia (5%). Other endocrine abnormalities are rare; however, isolated ACTH deficiency and GH hypersecretion or deficiency have also been described. Treatment for empty sella syndrome is focused on hormone replacement and/or dopamine agonists for hyperprolactinemia in the anovulatory patient.
Sheehan syndrome was initially described by Sheehan in 1939 as postpartum pituitary necrosis that results from significant intrapartum or postpartum hemorrhage or shock. It is considered the most common cause of panhypopituitarism in women of childbearing age.  During pregnancy, the anterior pituitary lactotrophs double in size. As a result, the demand for oxygen is greater, and the response to hypotension from hemorrhage is magnified.
Rapid hypotension from hemorrhage can interrupt the venous return to the gland and result in necrosis. The initial presenting sign of panhypopituitarism is usually failure to lactate postpartum, followed by amenorrhea, loss of pubic or axillary hair, secondary adrenal insufficiency, anorexia, lethargy, and weight loss. These symptoms are often delayed, and the degree of hypopituitarism varies. Slow clinical progression could suggest other factors involved in the pathogenesis of the disease, such as autoimmunity from antigens released from an infarcted gland. 
The diagnosis is confirmed based on the history and the results from the tests of anterior pituitary reserve: GH, ACTH, prolactin, TSH, LH, and FSH, all of which are found in very low levels. GH deficiency is the most common (90%), followed by ACTH (66%), LH/FSH (65%), and TSH (42%). Posterior pituitary involvement is rare, with central diabetes insipidus occurring in fewer than 5% of cases.  The treatment of Sheehan syndrome is based on appropriate hormone replacement. In patients receiving gonadotropins, successful ovulation and eventual pregnancy is common.
Pituitary apoplexy is a life-threatening disorder characterized by an acute massive infarction of the pituitary gland; it is a medical emergency that usually results from preexisting, endocrinologically inactive adenomas or tumors of the pituitary gland. The extent of hemorrhage, edema, and infarction of the gland determines the degree of compression of adjacent structures and subsequent neurologic damage. Patients typically present with acute onset of the triad of excruciating, localized retro-orbital headache (95%); nausea and vomiting (65%); and ophthalmoplegia (78%) secondary to compression and stretching of the meninges adjacent to the sella. The tumor expansion can also cause visual field defects and loss of pituitary function, demonstrable by low levels of GH, ACTH, LH/FSH, and TSH.
Management of this condition involves immediate administration of cortisol, supportive measures, and surgical intervention and decompression of the sella through a transsphenoidal approach. Studies have shown that patients who undergo surgical decompression within 1 week of the infarction have significant return of their visual defects compared with those undergoing delayed intervention.  The mortality rate accompanying this condition is high when exogenous cortisol is not administered after recognition of an ACTH deficiency. For patients with anovulation, treatment is supportive. Studies of amenorrheic adolescents who undergo surgical intervention for infarcted microadenomas have shown an 80% postsurgical improvement in endocrine function. 
Approximately 10% of all intracranial tumors are pituitary adenomas, with hypersecretion of biologically active hormones. The most common endocrinopathies are acromegaly due to GH excess, Cushing disease due to ACTH excess, and amenorrhea/galactorrhea syndrome due to prolactin excess (prolactinoma). Elevated gonadotropin levels can also result from gonadotropin-secreting pituitary adenomas. However, these rare adenomas are not associated with amenorrhea and usually secrete the beta subunit of FSH and rarely LH. The most common of the pituitary adenomas are prolactinomas.
These tumors are rarely life threatening; they result in amenorrhea, galactorrhea, and/or visual defects due to impingement of the optic chiasm from the space-occupying characteristics of the tumor. Previously, prolactinomas were thought to arise from dysregulation of prolactin due to the idiopathic attenuation of hypothalamic dopamine. Recent studies have described a genetic basis for tumor development. Prolactinomas are now thought to arise from proliferation of a single mutated lactotroph (prolactin-producing cell), usually in the lateral wing of the pituitary gland. These tumors have been found to occur in 20% of patients with multiple endocrine neoplasia syndrome, type 1 (MEN 1). 
Women who present with amenorrhea/galactorrhea syndrome should undergo laboratory testing for prolactin. levels of more than 250 ng/mL usually indicate prolactin-secreting adenomas, and levels of less than 150 ng/mL are usually secondary to large nonsecreting tumors of the pituitary. MRI or CT scanning with contrast can be used to help confirm diagnosis; however, both techniques have a high false-positive rate because they detect small nonsecreting tumors, cysts, or infarcts. Visual field testing is performed on symptomatic patients.
Treatment is reserved for women who experience either effects of tumor size or effects of hyperprolactinemia.  Most patients with microadenomas (< 10 mm) are managed conservatively with serial prolactin levels and follow-up MRI if they become symptomatic with headache or if prolactin levels rise significantly. Macroadenomas (>10 mm) may require more aggressive interventions, such as surgery or irradiation. Medical therapy with dopamine agonist therapy (eg, bromocriptine, cabergoline) can be used in patients with anovulatory menstrual cycles, decreased libido, sexual dysfunction, hirsutism, and osteoporosis. For women desiring fertility, bromocriptine is typically used until the fourth week of pregnancy. Cabergoline is not used for ovulation induction because of the lack of significant data on its possible adverse effects or teratogenicity in pregnancy.
Other indications for medical treatment include decreased libido, sexual dysfunction, hirsutism, and galactorrhea.
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].