Gynecology_Novak

Gynecology_Novak. A deletion of a portion of the X chromosome may be present in patients with POI. The Xq21-28 region is critical (7,88). Several genes in this region are identified as the cause of early ovarian insufficiency in humans. Examples include the POF1B gene located at Xq21, the DIAPH2 gene located at distal Xq21, and the XPNPEP2 gene located at Xq25 (89,90). The specific functions of these genes require further investigation. In addition, a mutation of the BMP15 gene located at Xp11.2 is identified in patients with premature ovarian failure (91).


Gynecology_Novak

Gynecology_Novak. An autosomal recessive form of premature ovarian failure is associated with hearing loss in Perrault syndrome (92). Mutations in FOXL2 causes ovarian failure and ptosis (93). Familial ovarian failure is inherited by dominant Mendelian inheritance in rare cases (94). Numerous genetic mutations leading to ovarian insufficiency are identified and many more are likely to be discovered (95,96). Other than the FMR1 premutation described next, no one mutation is particularly common.


Gynecology_Novak

Gynecology_Novak. Fragile X Carriers Fragile X syndrome, the most common cause of inherited (X-linked) intellectual disability, is caused by inactivation of the FMR1 (fragile X mental retardation 1) gene located on Xq27.3. This inactivation occurs as a result of expansion of a cytosine-guanine-guanine (CGG) triplet repeat of more than 200 copies (97). FMR1 premutation carriers (typically defined as greater than 55 but under 200 CGG repeats) may have primary ovarian insufficiency and impaired fertility. The prevalence of POI in women who carry the FMR1 premutation is estimated to be between 13% and 26%. The risk of having POI appears to increase with increasing premutation repeat size between 59 and 99. It is possible that there is an increased risk of POI among women who carry intermediate-size allele (approximately 41 to 58 repeats), but this is not conclusively proven. The risk plateaus or decreases for women with repeat sizes of 100. Interestingly, women with full mutations (200 or more CGG repeats)


Gynecology_Novak

Gynecology_Novak. 41 to 58 repeats), but this is not conclusively proven. The risk plateaus or decreases for women with repeat sizes of 100. Interestingly, women with full mutations (200 or more CGG repeats) are not at higher risk for POI. It is hypothesized that expression of abnormal FMR1 mRNA produced by patients with the premutation causes dysfunction in the ovary, which does not occur when the FMR1 gene is inactivated and not transcribed. The incidence of having a premutation is 0.8% to 7.5% of women with sporadic POI and up to 13% of women with familial POI.


Gynecology_Novak

Gynecology_Novak. FMR1 premutations carried by women are unstable and can expand in the next generation to transmit fragile X syndrome to male offspring, especially if women have more than 100 repeats. The smallest repeat to expand to the full mutation in one generation is approximately 59. In contrast to potential expansion in women, the repeat sequence is transmitted from fathers to daughters in a relatively stable manner.


Gynecology_Novak

Gynecology_Novak. Iatrogenic Causes of Primary Ovarian Insufficiency Radiation, chemotherapy (especially alkylating agents such as cyclophosphamide) (98), surgical interference with ovarian blood supply, and infections can cause ovarian failure from early loss of follicles. A radiation dose of 800 cGy causes sterility in most individuals. Ovarian failure can be caused by as little as 150 cGy in some patients, especially if they are older than 40 years of age with limited ovarian reserve. In an evaluation of ovarian function in 100 childhood cancer survivors, 17 had premature ovarian failure. Those with spontaneous menses had smaller ovarian volume, fewer antral follicles, and lower inhibin B levels when compared with controls (99). Ovarian suppression with GnRH agonists and oral contraceptives to reduce the risk of ovarian failure was attempted with limited success (100,101). Cigarette smoking decreases the age at which menopause will occur. But smoking would not be expected to be the primary cause of


Gynecology_Novak

Gynecology_Novak. risk of ovarian failure was attempted with limited success (100,101). Cigarette smoking decreases the age at which menopause will occur. But smoking would not be expected to be the primary cause of amenorrhea occurring before the age of 40.


Gynecology_Novak

Gynecology_Novak. Infections In rare cases, mumps was associated with premature ovarian failure (102). Women with human immunodeficiency virus (HIV) infection may prematurely lose ovarian function compared to women without HIV infection (103). Cytomegalovirus was shown postmortem to cause oophoritis, but premature ovarian failure had not yet developed clinically in the patient, so the relationship of cytomegalovirus to ovarian failure remains unclear (104).


Gynecology_Novak

Gynecology_Novak. Autoimmune Disorders In one series, 4% of women with POI were noted to have steroidogenic cell immunity with lymphocytic oophoritis as the mechanism for follicle dysfunction (105). Autoimmune lymphocytic oophoritis is associated with a theca cell infiltrate that spares granulosa cells (106). Ultrasound examination reveals the presence of numerous ovarian follicles, despite elevated serum FSH levels and hypoestrogenism (82). Ovarian antibody testing is not clinically reliable for diagnosing the disorder, as women with biopsy-proven autoimmune oophoritis may have a negative test for ovarian antibody. However, women with autoimmune lymphocytic oophoritis appear to reliably test positive for adrenal antibodies. The most readily available antibody is the 21-hydroxylase antibody (by immunoprecipitation). Ideally, antibody to the adrenal gland itself, as assessed by indirect immunoﬂuorescence, is reasonable to test if available. Testing for 21-hydroxylase antibody is strongly recommended for


Gynecology_Novak

Gynecology_Novak. Ideally, antibody to the adrenal gland itself, as assessed by indirect immunoﬂuorescence, is reasonable to test if available. Testing for 21-hydroxylase antibody is strongly recommended for women who are determined to have POI because women who test positive for this antibody are at risk for potentially fatal hypoadrenalism. Signs that suggest a risk for potentially fatal adrenal insufficiency include hyperpigmentation, weakness, nausea, vomiting, diarrhea, and weight loss.


Gynecology_Novak

Gynecology_Novak. POI may be part of a polyglandular autoimmune syndrome. Antibodies are present in a variable number of patients with POI, depending on the autoimmune studies performed. One study showed that 92% of patients with premature ovarian failure had autoantibodies (107). Only 20% of these patients exhibited signs of immunologic dysfunction, most frequently in the form of a thyroid disorder that is common in the general population of women who do not have POI. Presence of antithyroid antibodies does not confirm that there is an autoimmune cause for POI. Rarely, POI is associated with myasthenia gravis, idiopathic thrombocytopenia purpura, rheumatoid arthritis, vitiligo, autoimmune hemolytic anemia, diabetes mellitus, and other autoimmune disorders (108–110).


Gynecology_Novak

Gynecology_Novak. Galactosemia Galactosemia is caused by a lack of functional galactose-1-phosphate uridyl transferase. Galactosemia is a rare cause of POI and is typically diagnosed in childhood prior to presentation with amenorrhea. Galactose metabolites appear to have toxic effects on ovarian follicles, causing their premature destruction (111). Cataracts and mental retardation are associated with galactosemia. There is evidence that heterozygote carriers of this disorder may have suboptimal ovarian function (112). Early dietary modification may delay but not prevent the ovarian failure (26).


Gynecology_Novak

Gynecology_Novak. Hypothalamic Tumors For normal menstruation to occur, the hypothalamus must be able to secrete GnRH, and the pituitary must be able to respond with production and release of FSH and LH. Tumors of the hypothalamus or pituitary, such as craniopharyngiomas, germinomas, tubercular or sarcoid granulomas, or dermoid cysts, may prevent appropriate hormonal secretion. Patients with these disorders may have neurologic abnormalities, and secretion of other hypothalamic and pituitary hormones may be abnormal. Craniopharyngiomas are the most common tumors. They are located in the suprasellar region and frequently cause headaches and visual changes. The surgical and radiologic treatment of tumors may in itself cause further abnormalities in hormone secretion (Table 30.4).


Gynecology_Novak

Gynecology_Novak. Pituitary Lesions Hypopituitarism is rare because a large portion of the gland must be destroyed before decreased hormonal secretion affects the patient clinically. The pituitary gland may be destroyed by tumors (nonfunctioning or hormone secreting), infarction, or infiltrating lesions such as lymphocytic hypophysitis, granulomatous lesions, and surgical or radiologic ablations. Sheehan syndrome is associated with postpartum necrosis of the pituitary resulting from a hypotensive episode that, in its severe form (pituitary apoplexy), presents with the patient in shock. The patient may develop a localized, severe, retro-orbital headache or abnormalities in visual fields and visual acuity. Patients with a mild form of postpartum pituitary necrosis cannot lactate, lose pubic and axillary hair, and do not menstruate after delivery.


Gynecology_Novak

Gynecology_Novak. Diabetic vasculitis and sickle cell anemia rarely manifest as pituitary failure. Hypopituitarism is associated with hyposecretion of ACTH and thyroid-stimulating hormone (TSH) and gonadotropins; therefore, thyroid and adrenal function must be evaluated. If hypopituitarism occurs before puberty, menses and secondary sexual characteristics will not develop. Growth hormone (GH), TSH, ACTH, and prolactin are secreted by the pituitary, and the excess production of each by pituitary tumors causes menstrual abnormalities. The menstrual abnormalities are caused by adverse effects of these hormones on the GnRH pulse generator and not by direct effects on the ovary. Prolactinomas are the most common hormone-secreting tumors in the pituitary, as described above. Table 30.4 Pituitary and Hypothalamic Lesions


Gynecology_Novak

Gynecology_Novak. Table 30.4 Pituitary and Hypothalamic Lesions Abnormal secretion of GnRH accounts for one-third of patients with amenorrhea (113). Chronic disease, malnutrition, stress, psychiatric disorders, eating disorders, and exercise inhibit GnRH pulses, thus altering the menstrual cycle (Table 30.5). Other hormonal systems that produce excess or insufficient hormones can cause abnormal feedback and adversely affect GnRH secretion. In hyperprolactinemia, Cushing disease (excess ACTH), and acromegaly (excess GH), excess pituitary hormones are secreted that inhibit GnRH secretion. It is uncommon to have functional hypothalamic amenorrhea without a secondary cause. Prognosis for recovery is better if the precipitating cause of the amenorrhea can be reversed (114).


Gynecology_Novak

Gynecology_Novak. When the decrease in GnRH pulsatility is severe, amenorrhea results. With less severe alterations in GnRH pulsatility, anovulation and oligomenorrhea can occur. The pulsatile secretion of GnRH is modulated by interactions with neurotransmitters and peripheral gonadal steroids. Endogenous opioids, corticotropin-releasing hormones (CRH), melatonin, and α-aminobutyric acid (GABA) inhibit the release of GnRH, whereas catecholamines, acetylcholine, and vasoactive intestinal peptide stimulate GnRH pulses. Dopamine and serotonin have variable effects (115).


Gynecology_Novak

Gynecology_Novak. Decreased leptin levels are associated with hypothalamic amenorrhea, regardless of whether it is caused by exercise, eating disorders, or idiopathic factors (116,117). Leptin is a hormone secreted by adipocytes that is involved in energy hemostasis. Receptors are found in the hypothalamus and bone, making it an excellent candidate for a modulator of menstrual function and bone mass. Levels correlate with nutritional changes and body mass index. Administration of leptin to women with hypothalamic amenorrhea increased levels of LH, estradiol, insulinlike growth factor-1 (IGF-1), and thyroid hormone. Ovulation and increased bone mass occurred in these patients (117). Weight loss occurring with leptin administration limits the utility of using leptin as a therapeutic agent. Table 30.5 Abnormalities Affecting Release of Gonadotropin-Releasing Hormone a Severity of the condition determines estrogen status—the more severe, the more likely to manifest as hypoestrogenism.


Gynecology_Novak

Gynecology_Novak. amenorrhea. Patients attempt to maintain their low body weight by food restriction, laxative abuse, and intense exercise. This is a life-threatening disorder with a mortality rate as high as 9%. Amenorrhea may precede, coincide, or follow the weight loss. Multiple hormonal patterns are altered. The 24-hour patterns of FSH and LH may show constantly low levels as seen in childhood or increased LH pulsatility during sleep consistent with the pattern seen in early puberty. Hypercortisolism is present despite normal ACTH levels, and the ACTH response to CRH administration is blunted. Circulating triiodothyronine (T3) is low, yet circulating inactive reverse T3 concentrations are high (118). Patients may develop cold and heat intolerance, lanugo hair, hypotension, bradycardia, and diabetes insipidus. They may have yellowish discoloration of the skin resulting from elevated levels of serum carotene caused by altered vitamin A metabolism.


Gynecology_Novak

Gynecology_Novak. Binge eating is associated with bulimia consisting of vomiting, laxative abuse, and diuretics to control weight. Signs of bulimia include tooth decay, parotid gland hypertrophy (chipmunk jowls), hypokalemia, and metabolic alkalosis (119). Weight Loss and Dieting Weight loss can cause amenorrhea even if weight does not decrease below normal. Loss of 10% body mass in 1 year is associated with amenorrhea. Some but not all of these women have an underlying eating disorder. Prognosis is good for the return of menses if the patients recover from the weight loss. Dieting without weight loss and changes in diet can lead to amenorrhea (114).


Gynecology_Novak

Gynecology_Novak. Exercise In patients with exercise-induced amenorrhea, there is a decrease in the frequency of GnRH pulses, which is assessed by measuring a decreased frequency of LH pulses. These patients are usually hypoestrogenic, but less severe alterations may cause minimal menstrual dysfunction (anovulation or luteal phase defect). The decrease in GnRH pulsatility can be caused by hormonal alterations, such as low levels of leptin or high levels of ghrelin, neuropeptide Y and corticotrophin-releasing hormone (120). Runners and ballet dancers are at higher risk for amenorrhea than swimmers (121). It was previously suggested that a minimum of 17% body fat is required for the initiation of menses and 22% body fat for the maintenance of menses (122). Studies suggest that inappropriately low caloric intake during strenuous exercise is more important than body fat (123). Higher-intensity training, poor nutrition, stress of competition, and associated eating disorders increase an athlete’s risk for


Gynecology_Novak

Gynecology_Novak. during strenuous exercise is more important than body fat (123). Higher-intensity training, poor nutrition, stress of competition, and associated eating disorders increase an athlete’s risk for menstrual dysfunction (124). Osteoporosis may result in stress fractures during training and lifelong increased fracture risk. Stress fractures most commonly occur in the weight-bearing cortical bone such as the tibia, metatarsal, fibula, and femur. These athletes may fail to reach peak bone mass and have abnormal bone mineralization.


Gynecology_Novak

Gynecology_Novak. Stress Stress-related amenorrhea can be caused by abnormalities in neuromodulation in hypothalamic GnRH secretion, similar to those that occur with exercise and anorexia nervosa. Excess endogenous opioids and elevations in CRH secretion inhibit the secretion of GnRH (115). These mechanisms are not fully understood but appear to be the common link between amenorrhea and chronic diseases, pseudocyesis, and malnutrition.


Gynecology_Novak

Gynecology_Novak. Obesity Most obese patients have normal menstrual cycles, but the percentage of women with menstrual disorders increases for women with obesity compared with women of normal weight. The menstrual disorder is more often irregular uterine bleeding with anovulation rather than amenorrhea. Obese women have an excess number of fat cells in which extraglandular aromatization of androgen to estrogen occurs. They have lower circulating levels of sex hormone–binding globulin, which allows a larger proportion of free androgens to be converted to estrone. Excess estrogen creates a higher risk for endometrial cancer for these women. The decrease in sex hormone–binding globulin allows an increase in free androgen levels, which initially are eliminated by an increased rate of metabolic clearance. This compensatory mechanism diminishes over time, and hirsutism can develop. Frequently, these patients are classified as having PCOS. Alterations in the secretion of endorphins, cortisol, insulin, growth


Gynecology_Novak

Gynecology_Novak. compensatory mechanism diminishes over time, and hirsutism can develop. Frequently, these patients are classified as having PCOS. Alterations in the secretion of endorphins, cortisol, insulin, growth hormone, and IGF-1 may interact with the abnormal estrogen and androgen feedback to the GnRH pulse generator to cause menstrual abnormalities.


Gynecology_Novak

Gynecology_Novak. Other Hormonal Factors The secretion of hypothalamic neuromodulators can be altered by feedback from abnormal levels of peripheral hormones. Excesses or deficiencies of thyroid hormone, glucocorticoids, androgens, and estrogens can cause menstrual dysfunction. Excess secretion of GH, TSH, ACTH, and prolactin from the pituitary gland can cause abnormal feedback inhibition of GnRH secretion, leading to amenorrhea. Growth hormone excess causes acromegaly, which may be associated with anovulation, hirsutism, and polycystic-appearing ovaries as a result of stimulation of the ovary by IGF-1. More commonly, GH excess is accompanied by amenorrhea, low gonadotropin levels, and elevated prolactin levels. Acromegaly is recognized by enlargement of facial features, hands, and feet; hyperhidrosis; visceral organ enlargement; and multiple skin tags. Cushing disease is caused by an ACTH-secreting pituitary tumor, which is manifested by truncal obesity, moon facies, hirsutism, proximal weakness,


Gynecology_Novak

Gynecology_Novak. visceral organ enlargement; and multiple skin tags. Cushing disease is caused by an ACTH-secreting pituitary tumor, which is manifested by truncal obesity, moon facies, hirsutism, proximal weakness, depression, and menstrual dysfunction.


Gynecology_Novak

Gynecology_Novak. Evaluation for Women with Amenorrhea in the Presence of Normal Pelvic Anatomy and Normal Secondary Sexual Characteristics A pregnancy test (urine or serum human chorionic gonadotropin [hCG]) should be performed in a reproductive-age woman who has amenorrhea with normal secondary sexual characteristics and a normal pelvic examination. If the results of the pregnancy test are negative, the evaluation of amenorrhea is as follows: 1. Clinical assessment of estrogen status 2. 3. 4. 5. Vaginal ultrasound for assessment of antral follicle count in the ovaries can be considered (may help establish the diagnosis of PCOS or suggest POI) 6. Imaging of the pituitary and hypothalamic assessment if prolactin is elevated or if hypothalamic amenorrhea is suspected (particularly if CNS symptoms are present or there is no clear explanation for hypothalamic amenorrhea). Assessment of Estrogen Status


Gynecology_Novak

Gynecology_Novak. Assessment of Estrogen Status The presence of vaginal dryness or hot ﬂashes increases the likelihood of a diagnosis of hypoestrogenism. A sample of vaginal secretions can be obtained during the physical examination, and mucosal estrogen response can be demonstrated by the presence of superficial cells. A serum estradiol level higher than 40 pg/mL is considered indicative of significant estrogen production, but interassay discrepancies often exist and serum estrogen levels can vary greatly on a day-today basis for a given woman. Vaginal ultrasound demonstrating a thin endometrium suggests that a patient is hypoestrogenic, unless there is reason to suspect that the patient lacks functional endometrium. A DEXA (dual-energy x-ray absorptiometry) scan to determine bone mineral density should be considered for a patient in whom long-term hypoestrogenism is suspected.


Gynecology_Novak

Gynecology_Novak. There is little utility in routine performance of a progestogen challenge test to determine the patient’s estrogen status. False positives and false negatives are common. Consideration should be given to thyroid disorders and hyperprolactinemia in women with amenorrhea because of the relatively common incidence of these conditions. 1. Sensitive TSH assays can be used to evaluate hypothyroidism and hyperthyroidism. Further evaluation of a thyroid disorder is required if abnormalities in TSH levels are found. Mild degrees of thyroid dysfunction are unlikely to cause amenorrhea. Given the general health implications of thyroid dysfunction and readily available treatments, routine assessment of TSH is reasonable for women with amenorrhea.


Gynecology_Novak

Gynecology_Novak. 2. Prolactin is most accurately obtained in a patient who is fasting and who has not had any recent breast stimulation to avoid concluding that a patient is hyperprolactinemic on the basis of a transient prolactin elevation. If a patient still has some menstrual cycles, it is advisable to obtain the prolactin level in the follicular phase. Assessment of serum FSH levels is required to determine whether the patient has hypergonadotropic, hypogonadotropic, or eugonadotropic amenorrhea. A circulating FSH level of greater than 25 to 40 mIU/mL indicated on at least two blood samples is indicative of hypergonadotropic amenorrhea. Hypergonadotropism implies that the cause of amenorrhea is ovarian insufficiency. The history should establish whether the cause of ovarian insufficiency is chemotherapy or radiation therapy.


Gynecology_Novak

Gynecology_Novak. One test that is likely to be performed increasingly frequently is serum AMH. AMH is a product of the granulosa cells. AMH levels are low in women with POI and high in women with PCOS. AMH may be used more commonly in the evaluation of amenorrhea, but its assessment is not yet part of routine evaluation. If the diagnosis of POI is confirmed, the patient should be tested for: 1. FMR1 premutation 2. Karyotype 3. 21-hydroxylase antibody.


Gynecology_Novak

Gynecology_Novak. If the diagnosis of POI is confirmed, the patient should be tested for: 1. FMR1 premutation 2. Karyotype 3. 21-hydroxylase antibody. FMR1 premutation testing will reveal women at risk for bearing a child with fragile X syndrome, which may be important information for other family members. The goal of the peripheral blood karyotype is to identify an absent or abnormal X chromosome and to identify whether or not any portion of a Y chromosome is present. In situ hybridization studies may prove the existence of Y chromosomal material with a Y-specific probe when the karyotype is normal and should be assessed if there are clinical signs to suggest that a Y-bearing cell line is present despite normal routine peripheral blood karyotype (125). It is important to identify Y chromosomal material so it may be removed to prevent malignant degeneration. Although commonly suggested that


Gynecology_Novak

Gynecology_Novak. Assessment of the Pituitary and Hypothalamus karyotype only be performed if the patient is under age 30, it should be noted that rare patients with Turner syndrome developed amenorrhea after age 35. In addition, some patients who present over the age of 30 may have actually had the onset of POI at a younger age but were unaware because of the use of oral contraceptives. Therefore, consideration should be given to performance of karyotype, regardless of the patient’s age. Testing for 21-hydroxylase antibody will identify women at risk for adrenal crisis. If a diagnosis of PCOS is suspected, the patient should have: 1. Documentation of hyperandrogenism (either by serum total testosterone and sex hormone binding globulin or free testosterone and/or by presence of physical findings such as acne, hirsutism, and androgenic alopecia), 2.


Gynecology_Novak

Gynecology_Novak. Serum 17-hydroxyprogesterone to exclude congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency, particularly if the patient is at increased risk (highest prevalence is among Ashkenazi Jews, Hispanics, Yugoslavs, Native American Inuits in Alaska, and Italians) (79), 3. If the diagnosis of PCOS is made, the patient should undergo a 2-hour oral glucose tolerance test and a fasting lipid profile. If the patient is hypoestrogenic and the FSH level is not high, pituitary and hypothalamic lesions should be excluded. 1. A complete neurologic examination may help localize a lesion. 2. Either CT or MRI scanning should be performed to confirm the presence or absence of a tumor. MRI will identify smaller lesions than CT; if a lesion is too small for identification by CT, it may be clinically insignificant. MRI offers the advantage of avoiding exposure to x-ray. 3.


Gynecology_Novak

Gynecology_Novak. 3. The patient’s history of weight changes, exercise, eating habits, and body image is an important factor in determining whether anorexia nervosa, malnutrition, obesity, exercise, or stress may be responsible for amenorrhea. Patients with certain specific clinical findings should undergo screening for other hormonal alterations: 1. Androgen levels should be assessed in any hirsute patient to ensure that adrenal and ovarian tumors are not present and to aid in the diagnosis of PCOS. 2. Acromegaly is suggested by coarse facial features, large doughy hands, and hyperhidrosis and may be confirmed by measuring IGF-1 levels. 3. In patients with truncal obesity, hirsutism, hypertension, and erythematous striae, Cushing syndrome should be ruled out by assessing 24-hour urinary cortisol levels or performing a 1-mg overnight dexamethasone suppression test or late night salivary cortisol (126). It is important to confirm that the patient is not taking exogenous glucocorticoid.


Gynecology_Novak

Gynecology_Novak. Treatment for Women with Amenorrhea in the Presence of Normal Pelvic Anatomy and Normal Secondary Sexual Characteristics


Gynecology_Novak

Gynecology_Novak. The treatment of nonanatomic causes of amenorrhea associated with normal secondary sexual characteristics varies widely according to the cause. The underlying disorder should be treated whenever possible. Patients who are pregnant may be counseled regarding the options for continued care. When thyroid abnormalities are detected, thyroid hormone, radioactive iodine, or antithyroid drugs may be administered as appropriate. When hyperprolactinemia is present, treatment may include discontinuation of contributing medications, treatment with dopamine agonists such as bromocriptine or cabergoline, and, rarely, surgery for particularly large pituitary tumors. When POI causes amenorrhea, hormone replacement may be considered to diminish symptoms and to prevent osteoporosis. Counseling regarding the risks and benefits of hormone replacement therapy is indicated. Gonadectomy is required when a Y cell line is present.


Gynecology_Novak

Gynecology_Novak. Surgical removal, radiation therapy, or a combination of both is advocated for treatment of CNS tumors other than prolactinomas. It may be necessary to treat individuals who have panhypopituitarism with various replacement regimens after all the deficits are elucidated. These regimens include estrogen and progestogen replacement for lack of gonadotropins, corticosteroid replacement for lack of ACTH, thyroid hormone for lack of TSH, and desmopressin acetate (1-deamino-8-D-AVP [DDAVP]) to replace vasopressin. The treatment of amenorrhea associated with hypothalamic dysfunction depends on the underlying cause: 1. Hormonally active ovarian tumors are surgically removed (rare). 2. Obesity, malnutrition or chronic disease, Cushing syndrome, and acromegaly should be specifically treated. 3. Stress-induced amenorrhea may respond to psychotherapy. 4.


Gynecology_Novak

Gynecology_Novak. 2. Obesity, malnutrition or chronic disease, Cushing syndrome, and acromegaly should be specifically treated. 3. Stress-induced amenorrhea may respond to psychotherapy. 4. Exercise-induced amenorrhea may improve with moderation of activity and weight gain, when appropriate. If hypoestrogenism persists, higher doses of estrogen may be needed in these women than in older menopausal women to maintain bone density. In addition, 1,200 to 1,500 mg of calcium and 400 to 800 IU of vitamin D daily are advised. Bisphosphonates do not improve bone density in amenorrheic athletes because it is lack of bone formation rather than increased resorption that causes the osteopenia. In addition, the use of bisphosphonates is not advised because they can be deposited into the bone, and long-term effects, especially during pregnancy, are unknown. 5.


Gynecology_Novak

Gynecology_Novak. 5. Treatment of eating disorders such as anorexia nervosa generally demands a multidisciplinary approach, with severe cases requiring hospitalization (127).


Gynecology_Novak

Gynecology_Novak. Chronic anovulation associated with PCOS may be treated after identifying the desires of the patient. Patients may be concerned about their lack of menstruation, not hirsutism, or infertility. The endometrium of these individuals should be protected from the environment of unopposed estrogen that accompanies the anovulatory state. Oral contraceptives are a good alternative for those patients who require contraception. For those patients who are not candidates for oral contraceptive use, cyclic administration of progestogen is advised. Progestogen withdrawal will occur if there is an adequate estrogenic environment to induce proliferation of the endometrium, and it is not sufficient to cause withdrawal bleeding in patients who are hypoestrogenic (e.g., those who have amenorrhea associated with anorexia nervosa). Women with PCOS may require treatment for insulin resistance, dyslipidemia, and obesity. Regular periodic screening with an oral glucose load test and lipid panel is


Gynecology_Novak

Gynecology_Novak. with anorexia nervosa). Women with PCOS may require treatment for insulin resistance, dyslipidemia, and obesity. Regular periodic screening with an oral glucose load test and lipid panel is recommended for women with PCOS. Reduction in weight in obese women with PCOS leads to improved pregnancy rates, decreases hirsutism, and improves glucose and lipid levels (79). Insulin-sensitizing medications such as metformin and cholesterol-lowering medications such as statins can be considered. Ovulation induction is performed if pregnancy is desired, as described below.


Gynecology_Novak

Gynecology_Novak. A common progestogen used to induce withdrawal bleeding and thus protect the endometrium from hyperplastic transformation is medroxyprogesterone acetate (10 mg for 12 to 14 days per month). Occasionally, ovulation may occur; therefore, patients should be made aware that pregnancy is possible, and appropriate contraceptive measures should be used. Because there is theoretical concern that medroxyprogesterone acetate used in early pregnancy may increase the incidence of pseudohermaphroditism, a pregnancy test should be obtained if a woman fails to have a withdrawal bleed (128). Alternatively, progesterone suppositories (50 to 100 mg) or oral micronized progesterone (200 mg) can be given for 12 to 14 days per month to protect the endometrium from hyperplasia and induce withdrawal bleeding. No increased incidence of birth defects is associated with the use of natural progesterone (129).


Gynecology_Novak

Gynecology_Novak. In hypoestrogenic individuals such as those with POI, estrogen replacement must be added to the progestogen for successful menstrual regulation and prevention of osteoporosis. The doses of estrogen needed for relief of symptoms in young women with POI are often higher than those that are used for older menopausal women (130). Women with POI (who would normally still be making hormone if the ovaries were functioning normally) are different from those reaching menopause at a median age of 51. Therefore, data regarding hormone therapy that were collected from women reaching menopause at the median age should not be extrapolated to younger women. Although there are no comparative data and no long-term prospectively collected data regarding hormone therapy for women with POI, the risks of hormone therapy are likely to be lower and the benefits potentially greater for younger women than for older women reaching menopause after the age of 50 (131).


Gynecology_Novak

Gynecology_Novak. When chronic anovulation is caused by congenital adrenal hyperplasia, glucocorticoid administration (i.e., dexamethasone 0.5 mg at bedtime) is sometimes successful in restoring the normal feedback mechanisms, thereby permitting regular menstruation and ovulation. Hirsutism Patients who have oligomenorrhea or amenorrhea resulting from chronic anovulation may have hirsutism. The most common cause of hirsutism and oligo-ovulation is PCOS. After ruling out androgen-secreting tumors and congenital adrenal hyperplasia, treatment may be aimed at decreasing coarse hair growth. Oral Contraceptives Oral contraceptives may be effective for hirsutism by decreasing ovarian androgen production and increasing circulating levels of sex hormone–binding globulin, leading to decreased free androgen in the circulation.


Gynecology_Novak

Gynecology_Novak. Antiandrogens Spironolactone decreases androgen production and competes with androgens at the androgen receptor. Side effects include diuresis and dysfunctional uterine bleeding. The use of spironolactone is typically combined with oral contraceptives to avoid irregular bleeding and to prevent pregnancy from occurring while on spironolactone. Flutamide is approved by the U.S. Food and Drug Administration (FDA) for adjuvant therapy in prostatic cancer and for treatment of hirsutism. Its effects are similar to those of spironolactone (132). Liver function should be monitored because of the rare complication of hepatotoxicity. Cyproterone acetate, a strong progestin and antiandrogen, is used abroad but is not available in the United States. It is usually administered in combination with ethinyl estradiol in an oral contraceptive. By decreasing circulating androgen and LH levels, and by inducing antagonism of androgen effects at the peripheral level, cyproterone acetate is effective in


Gynecology_Novak

Gynecology_Novak. estradiol in an oral contraceptive. By decreasing circulating androgen and LH levels, and by inducing antagonism of androgen effects at the peripheral level, cyproterone acetate is effective in treating hirsutism (133). Finasteride, a 5α-reductase inhibitor, is approved by the FDA for the treatment of benign prostatic hypertrophy (Proscar) and male pattern baldness (Propecia). It is effective in treating hirsutism, although perhaps is no more effective than other available agents (134,135). Its major advantage is that it is exceptionally well tolerated and may be used when side effects preclude the use of other therapeutic options for hirsutism.


Gynecology_Novak

Gynecology_Novak. All antiandrogens are teratogenic as they may lead to feminization of the external genitalia of a male fetus (ambiguous genitalia) if the patient should conceive while taking the medication. Therefore, antiandrogens are typically used in combination with oral contraceptives. GnRH Agonist Administration of GnRH agonist agents virtually eliminates ovarian steroid production, and estrogen-progestogen add-back therapy allows long-term administration and protection against osteoporosis. Eﬂornithine Hydrochloride Eﬂornithine hydrochloride is a topical cream that is approved by the FDA for use on the face and chin. Improvements in facial hirsutism may be seen in 4 to 8 weeks of twice-daily applications.


Gynecology_Novak

Gynecology_Novak. Ovulation Induction A large subset of patients with amenorrhea or oligomenorrhea and chronic anovulation seek care because they are unable to conceive (see Chapter 32). Ovulation induction therapy is generally the treatment of choice for such patients, but pretreatment counseling should be provided in sufficient detail to ensure realistic expectations. The patient should be provided with information regarding the chances of a successful pregnancy (considering age of the patient and treatment modality), potential complications (hyperstimulation and multiple gestation), expense, time, and psychological impact involved in completing the course of therapy. Treatment should be individualized (136).


Gynecology_Novak

Gynecology_Novak. Earlier studies raised the possibility of a relationship between ovulation induction and the risk of ovarian cancer (137,138). Ongoing studies are attempting to address this issue conclusively, but data support an increase of approximately 2.5-fold in ovarian cancer in patients with infertility, which appears unrelated to the use of ovulation-inducing drugs (139140). There is no conclusive evidence to link fertility drug use and ovarian cancer; thus, no change in current ovulation induction practices seems warranted at present (141). Pregnancy and use of oral contraceptives before or after childbearing may protect against ovarian cancer.


Gynecology_Novak

Gynecology_Novak. Clomiphene citrate is the usual first choice for ovulation induction in most patients because of its relative safety, efficacy, route of administration (oral), and relatively low cost (142). Clomiphene citrate is indicated primarily in patients with adequate levels of estrogen and normal levels of FSH and prolactin. It is generally ineffective in hypogonadotropic patients who already have a poor estrogen supply (143). Patients with inappropriate gonadotropin release (an increased LH-to-FSH ratio), such as that which occurs in PCOS, are candidates for therapy with clomiphene citrate. As many as 80% of certain patients can be expected to ovulate after clomiphene citrate therapy. Contraindications to the use of clomiphene citrate include pregnancy, liver disease, and preexisting ovarian cysts. Side effects include hot ﬂashes and poorly understood visual symptoms, which generally were viewed as an indication to discontinue subsequent clomiphene citrate use. The risk of multiple pregnancy


Gynecology_Novak

Gynecology_Novak. Side effects include hot ﬂashes and poorly understood visual symptoms, which generally were viewed as an indication to discontinue subsequent clomiphene citrate use. The risk of multiple pregnancy is increased with clomiphene citrate compared with an overall of risk of approximately 8% (142). The majority of multiple gestations are twins; triplets and higher order multiple gestations are rare.


Gynecology_Novak

Gynecology_Novak. The most commonly recommended treatment regimen for clomiphene citrate is 50 mg daily for 5 days, beginning on the third to fifth day of menstrual or withdrawal bleeding. Cycles may be monitored by measuring midluteal progesterone levels to assess ovulation. Ovulation may be confirmed by an appropriate rise of basal body temperature and menses occurring at the expected time after the temperature rise. Ultrasonographic monitoring to assess folliculogenesis may be helpful, especially when hCG is used to induce ovulation. Endometrial thinning caused by the antiestrogenic effects of clomiphene citrate may be detected with midcycle ultrasound. With these data, it is possible to immediately adjust the dose in the subsequent cycle if a given regimen is ineffective. Dosage increases of 50 mg per day are usually used, and more than 70% of conceptions occur at doses no higher than 100 mg per day for 5 days (144). Dosages higher than 150 mg per day for 5 days are usually ineffective, and


Gynecology_Novak

Gynecology_Novak. mg per day are usually used, and more than 70% of conceptions occur at doses no higher than 100 mg per day for 5 days (144). Dosages higher than 150 mg per day for 5 days are usually ineffective, and patients who remain anovulatory with this dosage should undergo further evaluation accompanied by changes in the therapeutic plan. Longer courses of clomiphene citrate therapy, and adjunctive therapy with glucocorticoids, are suggested if a patient does not ovulate with standard therapy (145).


Gynecology_Novak

Gynecology_Novak. Although a large randomized trial demonstrated that clomiphene alone is superior to metformin alone in achieving live birth in women with PCOS, a meta-analysis suggests that for some patients with PCOS, metformin and clomiphene combined may increase the likelihood of ovulation compared with clomiphene alone (146,147). Thinning of the endometrium at midcycle in the face of adequate midcycle estradiol and lack of success with repeated cycles of clomiphene are generally indications to consider injectable gonadotropins. Aromatase inhibitors, such as letrozole, were suggested as an option for ovulation induction (148).


Gynecology_Novak

Gynecology_Novak. Women with PCOS who do not ovulate or become pregnant with clomiphene citrate, and women with hypogonadotropic hypoestrogenic anovulation, may be candidates for therapy with injectable gonadotropins. Available preparations include recombinant FSH and LH and products purified from the urine of menopausal women (FSH or FSH-LH combinations). Administration protocols and dosages vary widely and should be adjusted to individual needs. Safe administration requires careful monitoring of ovarian response with ultrasonography and, in some cases, serial estradiol measurements. In general, gonadotropins are administered at a dose of 50 to 150 IU per day by subcutaneous injection for 3 to 5 days, after which time estradiol and follicular monitoring commence. In most cycles, gonadotropin is administered for 7 to 12 days. Ovulation is triggered by subcutaneous or intramuscular injection of 5,000 to 10,000 IU hCG or subcutaneous injection of 250 μgof recombinant hCG once the lead follicle reaches 16


Gynecology_Novak

Gynecology_Novak. for 7 to 12 days. Ovulation is triggered by subcutaneous or intramuscular injection of 5,000 to 10,000 IU hCG or subcutaneous injection of 250 μgof recombinant hCG once the lead follicle reaches 16 to 20 mm in diameter based on ultrasonographic assessments. Ovulation generally occurs approximately 38 to 40 hours after hCG administration. Luteal phase support is sometimes provided with the administration of progesterone supplementation or with additional injections of hCG.


Gynecology_Novak

Gynecology_Novak. The two major complications associated with induction of ovulation with gonadotropins are multiple pregnancy (10% to 30%) and ovarian hyperstimulation syndrome. The incidence of both of these complications can be reduced but not eliminated by careful monitoring. Cycles complicated by the recruitment of numerous follicles or by high estradiol levels may be canceled by withholding the ovulatory dose of hCG. Selected patients may be converted safely to in vitro fertilization. Because severe ovarian hyperstimulation syndrome is life-threatening and may lead to prolonged hospitalization, ovulation induction with gonadotropins generally is performed by experienced practitioners who devote a significant portion of their practice to the treatment of infertility.


Gynecology_Novak

Gynecology_Novak. Ovulation induction with pulsatile GnRH may be effective in patients who have chronic anovulation associated with low levels of estrogen and gonadotropins. For therapy to be successful, a functional ovary and pituitary gland must be present. Patients with ovarian or pituitary failure do not respond to GnRH therapy. To be effective, GnRH must be administered in a pulsatile fashion, either intravenously or subcutaneously by a programmable pump. Ovulation induction with GnRH, as compared with gonadotropins, is associated with a relatively low incidence of ovarian hyperstimulation and multiple births. In addition, the need for appropriate timing of the ovulatory dose of hCG is avoided because patients treated with pulsatile GnRH have an appropriately timed endogenous LH surge. Disadvantages are mainly related to maintaining the programmable pump and injection site and lack of availability of an appropriate pump in the United States. After ovulation, luteal phase support is necessary and


Gynecology_Novak

Gynecology_Novak. are mainly related to maintaining the programmable pump and injection site and lack of availability of an appropriate pump in the United States. After ovulation, luteal phase support is necessary and may be provided with hCG, progesterone, or continuation of the GnRH therapy.


Gynecology_Novak

Gynecology_Novak. For women with overt POI (also known as premature ovarian failure, as noted above), there is no good evidence to suggest that any treatment can increase the chance of conception with autologous oocytes (85). Treatments that were tried include ovulation induction with clomiphene or gonadotropin, pretreatment with high-dose estrogen or gonadotropinreleasing hormone agonist followed by expectant management or gonadotropin stimulation, standard-dose hormone therapy followed by gonadotropin, and corticosteroid pretreatment followed by gonadotropin. Administration of dehydroepiandrosterone (DHEA) is suggested for women with POI (149). It is uncertain whether the benefit seen in preliminary reports will stand the test of time.


Gynecology_Novak

Gynecology_Novak. If POI is diagnosed while a patient still has a significant supply of oocytes, fertility preservation could be considered if the patient is not able to consider conception at the time of diagnosis. In most cases, patients with prolonged amenorrhea are not diagnosed at a time when significant numbers of reproductively competent oocytes are present. Fertility preservation is an option for patients about to undergo gonadotoxic chemotherapy or if a patient is known (e.g., based on family history) to be at risk for POI. Either embryos or oocytes can be cryopreserved. There is more worldwide experience with cryopreservation of embryos. Improvements are occurring in techniques of oocyte and ovarian tissue cryopreservation (150,151).


Gynecology_Novak

Gynecology_Novak. Patients with POI who desire pregnancy will in most cases have a high chance of having a child with the help of oocyte donation. Oocytes from donors may be harvested after ovulation induction, fertilized with sperm from the intended father, and transferred into the recipient’s uterus after the endometrium is appropriately prepared with estrogen and progesterone. Special concern is warranted for women with Turner syndrome who appear to have a maternal mortality of at least 2% (58). Rupture of the aorta may occur even if an echocardiogram shows no dilatation (152). It is suggested that all women with Turner syndrome undergo a full cardiac evaluation, including a cardiac MRI at a center with expertise in cardiovascular imaging, and that pregnancy be contraindicated if the patient has known congenital cardiovascular disease (e.g., bicuspid aortic valve or aortic coarctation) or with aortic size greater than 2 cm/m2 (153). 1.


Gynecology_Novak

Gynecology_Novak. 1. Hoffman B, Bradshaw K. Delayed puberty and amenorrhea. Semin Reprod Med 2003;4:353–362. 2. The Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril 2008;90:S219–S225. 3. Rosen GF, Kaplan B, Lobo RA. Menstrual function and hirsutism in patients with gonadal dysgenesis. Obstet Gynecol 1988;17:677–680. 4. Turner HH. A syndrome of infantilism, congenital webbed neck, and cubitus-valgus. Endocrinology 1938;23:566–574. 5. Leppig KA, Disteche CM. Ring X and other structural X chromosome abnormalities: X inactivation and phenotype. Semin Reprod Med 2001;19:147–157. 6. Bondy CA, Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007;92:10–25. 7. Therman E, Susman B. The similarity of phenotypic effects caused by Xp and Xq deletion in the human female: a hypothesis. Hum Genet 1990;85:175–183. 8.


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Gynecology_Novak. 7. Therman E, Susman B. The similarity of phenotypic effects caused by Xp and Xq deletion in the human female: a hypothesis. Hum Genet 1990;85:175–183. 8. Zinn AR, Tonk VS, Chen Z, et al. Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1. Am J Hum Genet 1998;63:1757–1766. 9. Schmidt M, Du Sart D. Functional disomies of the X chromosome inﬂuence the cell selection and hence the X inactivation pattern in females with balanced X–autosome translocations: a review of 122 cases. Am J Med Genet 1992;42:161–169. 10. Ferguson-Smith MA. Karyotype-phenotype correlations in gonadal dysgenesis and their bearing on the pathogenesis of malformations. J Med Genet 1965;2:142–155. 11. Hawkins JR. Mutational analysis of SRY in XY females. Hum Mutat 1993;2:347–350. 12. Timmreck L, Reindollar R. Contemporary issues in primary amenorrhea. Obstet Gynecol Clin North Am 2003;30:287–302. 13.


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Gynecology_Novak. 12. Timmreck L, Reindollar R. Contemporary issues in primary amenorrhea. Obstet Gynecol Clin North Am 2003;30:287–302. 13. Jorgensen PB, Kjartansd´ottir KR, Fedder J. Care of women with XY karyotype: a clinical practice guideline. Fertil Steril 2010;94:105–115. 14. Foster JW, Dominguez-Steglich MA, Guioli S, et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 1994;372:525–530. 15. Wagner T, Wirth J, Meyer J, et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 1994;79:1111–1120. 16. Zanaria E, Bardoni B, Dabovic B, et al. Xp duplications and sex reversal. Philos Trans R Soc Lond B Biol Sci 1995;350:291–296. 17. Cotinot C, Pailhoux E, Jaubert F, et al. Molecular genetics of sex determination. Semin Reprod Med 2002;20:157–167. 18.


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Gynecology_Novak. 17. Cotinot C, Pailhoux E, Jaubert F, et al. Molecular genetics of sex determination. Semin Reprod Med 2002;20:157–167. 18. Barbaux S, Niaudet P, Gubler MC, et al. Donor splice-site mutations in WTI are responsible for Frasier syndrome. Nat Genet 1997;17:467–470. 19. MacLaughlin DT, Donahoe PK. Mechanisms of disease: sex determination and differentiation. N Engl J Med 2004;350:367–378. 20. Achermann JC, Ito M, Hindmarsh PC, et al. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 1999;22:125–126. 21. Warne GL, Kanumakala S. Molecular endocrinology of sex differentiation. Semin Reprod Med 2002;20:169–179. 22. Damiani D, Guedes DR, Fellous M, et al. Ullrich-Turner syndrome: relevance of searching for Y chromosome fragments. J Pediatr Endocrinol 1999;12:827–831. 23.


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Gynecology_Novak. 22. Damiani D, Guedes DR, Fellous M, et al. Ullrich-Turner syndrome: relevance of searching for Y chromosome fragments. J Pediatr Endocrinol 1999;12:827–831. 23. Osipova GR, Karmanov ME, Kozlova SI, et al. PCR detection of Y-specific sequences in patients with Ullrich-Turner syndrome: clinical implications and limitations. Am J Med Genet 1998;76:283–287. 24. Bose HS, Sugawara T, Strauss J, et al. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med 1996;335:1870–1878. 25. Touraine P, Beau I, Gougeon A, et al. New natural inactivation mutations of the follicle-stimulating hormone receptor: correlations between receptor function and phenotype. Mol Endocrinol 1999;13:1844–1854. 26. Adashi EY, Hennebold JD. Mechanisms of disease: single gene mutations resulting in reproductive dysfunction in women. N Engl J Med 1999;340:709–718. 27.


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Gynecology_Novak. 26. Adashi EY, Hennebold JD. Mechanisms of disease: single gene mutations resulting in reproductive dysfunction in women. N Engl J Med 1999;340:709–718. 27. Goldsmith O, Soloman DH, Horton R. Hypogonadism and mineralocorticoid excess: the 17-hydroxylase deficiency syndrome. N Engl J Med 1967;277:673–677. 28. Zirilli L, Rochira V, Diazzi C, et al. Human models of aromatase deficiency. J Steroid Biochem Molecular Biol 2008;109:212–218. 29. Bulun SE. Clinical review 78: aromatase deficiency in women and men: would you have predicted the phenotypes? J Clin Endocrinol Metab 1996;81:867–871. 30. Mullis PE, Yoshimura N, Kuhlmann B, et al. Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries and bone densitometry in childhood. J Clin Endocrinol Metab 1997;82:1739– 1745. 31.


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Gynecology_Novak. 31. Latronico AC, Anasti M, Arnhold I, et al. Testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene. N Engl J Med 1996;334:507– 512. 32. Latronico AC. Naturally occurring mutations of the luteinizing hormone receptor gene affecting reproduction. Semin Reprod Med 2000;18:17–20. 33. Tapanainen JS, Vaskivup T, Aittomaki K, et al. Inactivating FSH receptor mutations and gonadal dysfunction. Mol Cell Endocrinol 1998;145:129–135. 34. Barrett A, Nicholls J, Gibson B. Late effects of total body irradiation. Radiother Oncol 1987;9:131–135. 35. Ahmed SR, Shalet SM, Campbell RH, et al. Primary gonadal damage following treatment of brain tumors in childhood. J Pediatr 1983;103:562–565. 36. Fechner A, Fong S, McGovern P. A review of Kallmann syndrome: genetics pathophysiology, and clinical management. Obstet Gynecol Sur 2008;63:189–194. 37.


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Gynecology_Novak. 36. Fechner A, Fong S, McGovern P. A review of Kallmann syndrome: genetics pathophysiology, and clinical management. Obstet Gynecol Sur 2008;63:189–194. 37. Banna M. Craniopharyngioma: based on 160 cases. Br J Radiol 1976;49:206–223. 38. Thomsett JJ, Conte FA, Kaplan SL, et al. Endocrine and neurologic outcome in childhood craniopharyngioma: review of effective treatment in 42 patients. J Pediatr 1980;97:728–735. 39. Peterson RE, Imperato-McGinley J, Gautier T, et al. Male pseudohermaphroditism due to steroid 5α reductase deficiency. Am J Med 1977;62:170–191. 40. Cohen DP. Molecular evaluation of the gonadotropin-releasing hormone receptor. Semin Reprod Med 2000;18:11–16. 41. Beranova M, Oliveira LM, Bedecarrats GY, et al. Prevalence, phenotypic spectrum and modes of inheritance of gonadotropinreleasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2001;86:1580– 1588. 42.


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Gynecology_Novak. 42. Layman LC, Lee EJ, Peak DB, et al. Brief report: delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone (beta)-subunit gene. N Engl J Med 1997;337:607– 611. 43. Matthews CH, Borgato S, Beck-Peccoz P. Primary amenorrhea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone. Nat Genet 1993;5:83–86. 44. Kulin HE, Bwibo N, Mutie D, et al. Gonadotropin excretion during puberty in malnourished children. J Pediatr 1984;105:325–328. 45. Cumming DC, Rebar RW. Exercise in reproductive function in women. Am J Intern Med 1983;4:113–125. 46. Ferraris J, Saenger P, Levine L, et al. Delayed puberty in males with chronic renal failure. Kidney Int 1980;18:344–350. 47. Siris ES, Leventhal BG, Vaitukaitis JL. Effects of childhood leukemia and chemotherapy on puberty and reproductive function in girls. N Engl J Med 1976;294:1143–1146. 48.


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Gynecology_Novak. 47. Siris ES, Leventhal BG, Vaitukaitis JL. Effects of childhood leukemia and chemotherapy on puberty and reproductive function in girls. N Engl J Med 1976;294:1143–1146. 48. Copeland KC, Underwood LE, Van Wyk JJ. Marijuana smoking and pubertal arrest. Pediatrics 1980;96:1079–1080. 49. Patton ML, Woolf PD. Hyperprolactinemia and delayed puberty: a report of three cases and their response to therapy. Pediatrics 1983;71:572–575. 50. Asherson RA, Jackson WPU, Lewis B. Abnormalities of development associated with hypothalamic calcification after tuberculous meningitis. BMJ 1965;2:839–843. 51. Alper MM, Garner PR, Seibel MM. Premature ovarian failure. J Reprod Med 1986;8:699–708. 52. Davajan V, Kletzky OA. Primary amenorrhea: phenotypic female external genitalia. In: Mishell DR, Davajan V, Lobo RA, eds. Infertility contraception and reproductive endocrinology. 3rd ed. Cambridge, MA: Blackwell Scientific Publications, 1991:356–371. 53.


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Gynecology_Novak. 53. Lichter AS, Wara WM, Sheline GE, et al. The treatment of craniopharyngiomas. Int J Radiat Oncol 1977;2:675–683. 54. Wara WM, Fellows FC, Sheline GE, et al. Radiation therapy for pineal tumors and suprasellar germinomas. Radiology 1977;124:221–223. 55. Koenig MP, Suppinger K, Leichti B. Hyperprolactinemia as a cause of delayed puberty: successful treatment with bromocriptine. J Clin Endocrinol Metab 1977;45:825–828. 56. Golden NH. Eating disorders in adolescence: what is the role of hormone replacement therapy? Curr Opinion Obstet Gynecol 2007;19:434–439. 57. Rosen GF, Vermesh M, d’Ablain GG, et al. The endocrinologic evaluation of a 45X true hermaphrodite. Am J Obstet Gynecol 1987;157:1272–1273. 58. Karnis MF, Zimon AE, Lalwani SI, et al. The risk of death in pregnancy achieved through oocyte donation in patients with Turner syndrome: a national survey. Fertil Steril 2003;80:498–501. 59.


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Gynecology_Novak. 58. Karnis MF, Zimon AE, Lalwani SI, et al. The risk of death in pregnancy achieved through oocyte donation in patients with Turner syndrome: a national survey. Fertil Steril 2003;80:498–501. 59. Buttram VC Jr, Gibbons WE. M¨ullerian anomalies: a proposed classification. Fertil Steril 1979;32:40–46. 60. Laufer MR. Congenital absence of the vagina: in search of the perfect solution. When, and by what technique, should a vagina be created? Curr Opin Obstet Gynecol 2002;14:441–444. 61. Fore SR, Hammond CB, Parker RT, et al. Urology and genital anomalies in patients with congenital absence of the vagina. Obstet Gynecol 1975;46:410–416. 62. Gell JS. M¨ullerian anomalies. Semin Reprod Med 2003;21:375–388. 63. Griffin JE, Edwards C, Madden JD, et al. Congenital absence of the vagina. Ann Intern Med 1976;85:224–236. 64.


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Gynecology_Novak. 62. Gell JS. M¨ullerian anomalies. Semin Reprod Med 2003;21:375–388. 63. Griffin JE, Edwards C, Madden JD, et al. Congenital absence of the vagina. Ann Intern Med 1976;85:224–236. 64. Cramer DW, Goldstein DP, Fraer C, et al. Vaginal agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome) associated with the N314D mutation of galactose-1-phosphate uridyl transferase (GALT). Mol Hum Reprod 1996;2:145–148. 65. Klein SM, Garcia CR. Asherman’s syndrome: a critique and current review. Fertil Steril 1973;24:722–735. 66. Suttan C, Lumbroso S, Paris F, et al. Disorders of androgen action. Semin Reprod Med 2002;20:217–224. 67. McPhaul MJ. Androgen receptor mutations and androgen insensitivity. Mol Cell Endocrinol 2002;198:61–67. 68. Amrhein JA, Meyer WJ III, Jones HW Jr, et al. Androgen insensitivity in man: evidence of genetic heterogeneity. Proc Natl Acad Sci USA 1976;73:891–894. 69. Rock JA. Anomalous development of the vagina. Semin Reprod Endocrinol 1986;4:1–28. 70.


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Gynecology_Novak. 69. Rock JA. Anomalous development of the vagina. Semin Reprod Endocrinol 1986;4:1–28. 70. Frank RT. The formation of an artificial vagina. Am J Obstet Gynecol 1938;35:1053–1055. 71. Rock JA, Zacur HA, Diugi AM, et al. Pregnancy success following surgical correction of imperforate hymen and complete transverse vaginal septum. Obstet Gynecol 1982;59:448–451. 72. Williams EA. Uterovaginal agenesis. Ann R Coll Surg Engl 1976;58:266–277. 73. Ingram JN. The bicycle seat stool in the treatment of vaginal agenesis and stenosis: a preliminary report. Am J Obstet Gynecol 1982;140:867–873. 74. McIndoe A. The treatment of congenital absence and obliterative condition of the vagina. Br J Plast Surg 1950;2:254–267. 75. Rock JA, Breech LL. Surgery for anomalies of the M¨ullerian ducts. In: Rock JA, Jones HW, eds. TeLinde’s operative gynecology. 10th ed. Philadelphia, PA: JB Lippincott, Williams & Wilkins, 2008. 76.


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Gynecology_Novak. 76. Conte FA, Grumbach MM. Pathogenesis, classification, diagnosis, and treatment of anomalies of sex. In: De Groot LJ, ed. Endocrinology. Philadelphia, PA: WB Saunders, 1989:1810–1847. 77. Manuel M, Katayama KP, Jones HW Jr. The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am J Obstet Gynecol 1976;124:293–300. 78. Doody KM, Carr BR. Amenorrhea. Obstet Gynecol Clin North Am 1990;17:361–387. 79. ACOG Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin No. 108: polycystic ovary syndrome. Obstet Gynecol 2009;114:936–949. 80. 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;81:19–23. 81. Klibanski A. Clinical practice. Prolactinomas. N Engl J Med 2010;362:1219–1226. 82. Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med 2009;360:606–614. 83.


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Gynecology_Novak. 81. Klibanski A. Clinical practice. Prolactinomas. N Engl J Med 2010;362:1219–1226. 82. Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med 2009;360:606–614. 83. Welt CK. Primary ovarian insufficiency: a more accurate term for premature ovarian failure. Clin Endocrinol 2008;68:499–509. 84. Rebar RW, Connolly HV. Clinical features of young women with hypergonadotropic amenorrhea. Fertil Steril 1990;53:804–810. 85. van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update 1999;5:483–492. 86. Singh RP, Carr DH. The anatomy and histology of XO human embryos and fetuses. Anat Rec 1966;155:369–383. 87. Tartaglia N, Howell S, Sutherland A, et al. A review of trisomy X (47,XXX). Orphanet J Rare Dis 2010;5:8. 88.


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Gynecology_Novak. 87. Tartaglia N, Howell S, Sutherland A, et al. A review of trisomy X (47,XXX). Orphanet J Rare Dis 2010;5:8. 88. Krauss CM, Tarskoy RN, Atkins L, et al. Familial premature ovarian failure due to interstitial deletion of the long arm of the X chromosome. N Engl J Med 1987;317:125–131. 89. Bione S, Sala C, Manzini C, et al. A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure: evidence for conserved function in oogenesis and implications for human sterility. Am J Hum Genet 1998;62:533–541. 90. Pruiett RL, Ross JL, Zinn AR. Physical mapping of nine Xq trans-location breakpoints and identification of XPNPEP2 as a premature ovarian failure candidate gene. Cytogenet Cell Genet 2000;89:44–50. 91. DiPasquale E, Beck-Peccoz P, Persani L. Hypergonadotropic ovarian failure associated with an inherited mutation of hormone loss morphogenetic protein-15(BMP15) gene. Am J Hum Genet 2004;75:106–111. 92.


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Gynecology_Novak. 92. Nishi Y, Hamamoto K, Kafiyama M, et al. The Perrault syndrome: clinical report and review. Am J Med Genet 1988;31:623–629. 93. Crisponi L, Deiana M, Loi A, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 2001;27:159–166. 94. Mattison DR, Evan MI, Schwimmer WB. Familial premature ovarian failure. Am J Hum Genet 1984;36:1341–1348. 95. Simpson JL. Genetic and phenotypic heterogeneity in ovarian failure: overview of selected candidate genes. Ann N Y Acad Sci 2008;1135:146–154. 96. Skillern A, Rajkovic A. Recent developments in identifying genetic determinants of premature ovarian failure. Sex Dev 2008;2:228–243. 97. Wittenberger MD, Hagerman RJ, Sherman SL, et al. The FMR1 premutation and reproduction. Fertil Steril 2007;87:456–465. 98. Stillman RJ, Schinfeld JS, Schiff I, et al. Ovarian failure in long term survivors of childhood malignancy.Am J Obstet Gynecol 1981;139:62–66. 99.


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Gynecology_Novak. 98. Stillman RJ, Schinfeld JS, Schiff I, et al. Ovarian failure in long term survivors of childhood malignancy.Am J Obstet Gynecol 1981;139:62–66. 99. Larsen EC, Muller J, Schmiegelow K, et al. Reduced ovarian function in long-term survivors of radiation-and chemotherapy-treated childhood cancer. J Clin Endocrinol Metab 2003;88:5307–5314. 100. Whitehead E, Shalet SM, Blackledge G, et al. The effect of combination chemotherapy on ovarian function in women treated for Hodgkin’s disease. Cancer 1983;52:988–993. 101. Waxman JH, Ahmed R, Smith D, et al. Failure to preserve fertility in patients with Hodgkin’s disease. Cancer Chemother Pharmacol 1987;19:159–162. 102. Morrison JC, Givens JR, Wiser WL, et al. Mumps oophoritis: a cause of premature ovarian failure. Fertil Steril 1975;26:655– 659. 103. Santoro N, Fan M, Maslow B, Schoenbaum E. Women and HIV infection: the makings of a midlife crisis. Maturitas 2009;64:160– 164. 104.


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Gynecology_Novak. 103. Santoro N, Fan M, Maslow B, Schoenbaum E. Women and HIV infection: the makings of a midlife crisis. Maturitas 2009;64:160– 164. 104. Williams DJ, Connor P, Ironside JW. Premenopausal cytomegalovirus oophoritis. Histopathology 1990;16:405–407. 105. Bakalov VK, Anasti JN, Calis KA, et al. Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure. Fertil Steril 2005;84:958– 965. 106. Welt CK. Autoimmune oophoritis in the adolescent. Ann N Y Acad Sci 2008;1135:118–122. 107. Mignot MH, Shoemaker J, Kleingel M, et al. Premature ovarian failure. I: the association with autoimmunity. Eur J Obstet Gynecol Reprod Biol 1989;30:59–66. 108. Jones GS, de Moraes-Ruehsen M. A new syndrome of amenorrhea in association with hypergonadotropism and apparently normal ovarian follicular apparatus. Am J Obstet Gynecol 1969;104:597–600. 109.


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Gynecology_Novak. Jones GS, de Moraes-Ruehsen M. A new syndrome of amenorrhea in association with hypergonadotropism and apparently normal ovarian follicular apparatus. Am J Obstet Gynecol 1969;104:597–600. 109. Kim MH. “Gonadotropin-resistant ovaries” syndrome in association with secondary amenorrhea. Am J Obstet Gynecol 1974;120:257– 263. 110. de Moraes-Ruehsen M, Blizzard RM, Garcia-Bunuel R, et al. Autoimmunity and ovarian failure. Am J Obstet Gynecol 1972;112:693–703. 111. Kaufman FR, Kogut MD, Donnell GN, et al. Hypergonadotropic hypogonadism in female patients with galactosemia. N Engl J Med 1981;304:994–998. 112. Cramer DW, Harlow BL, Barbieri RL, et al. Galactose1-phosphate uridyl transferase activity associated with age at menopause and reproductive history. Fertil Steril 1989;51:609–615. 113. Reindollar RH, Novak M, Tho SP. Adult onset amenorrhea: a study of 262 patients. Am J Obstet Gynecol 1986;155:531–543. 114.


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Gynecology_Novak. 113. Reindollar RH, Novak M, Tho SP. Adult onset amenorrhea: a study of 262 patients. Am J Obstet Gynecol 1986;155:531–543. 114. Perkins RB, Hall JE, Martin KA. Aetiology, previous menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhea. Hum Reprod 2001;16:2198– 2205. 115. Genazzani AR, Petragtia F, DeRamundo BM, et al. Neuroendocrine correlates of stress-related amenorrhea. Ann N Y Acad Sci 1991;626:125–129. 116. Warren MP, Voussoughian F, Geer EB, et al. Functional hypothalamic amenorrhea: hypoleptinemia and disordered eating. J Clin Endocrinol Metab 1999;84:873–877. 117. Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;351:987–997. 118. Herzog DB, Copeland PM. Eating disorders. N Engl J Med 1985;313:295–303. 119. Mehler PS. Clinical practice: bulimia nervosa. N Engl J Med 2003;349:875–881. 120.


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Gynecology_Novak. 118. Herzog DB, Copeland PM. Eating disorders. N Engl J Med 1985;313:295–303. 119. Mehler PS. Clinical practice: bulimia nervosa. N Engl J Med 2003;349:875–881. 120. Gordon CM. Functional hypothalmic amenorrhea. N Engl J Med 2010;363:365–371. 121. Desouza MJ, Metzger DA. Reproductive dysfunction in amenorrheic athletic and anorexic patients: a review. Med Sci Sports Exerc 1991;23:995–1007. 122. Frisch RE, McArthur JW. Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science 1974;185:949–995. 123. Laughlin GA, Yen SS. Nutritional and endocrine-metabolic aberrations in amenorrheic athletes. J Clin Endocrinol Metab 1997;81:4301–4309. 124. Highet R. Athletic amenorrhea: an update on a etiology, complications and management. Sports Med 1989;7:82–108. 125.


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Gynecology_Novak. 124. Highet R. Athletic amenorrhea: an update on a etiology, complications and management. Sports Med 1989;7:82–108. 125. Medlej R, Laboaccaro JM, Berta P, et al. Screening for Y-derived sex determining gene SRY in 40 patients with Turner syndrome. J Clin Endocrinol Metab 1992;75:1289–1292. 126. Newell-Price J. Diagnosis/differential diagnosis of Cushing’s syndrome: a review of best practice. Best Pract Res Clin Endocrinol Metab 2009;23:S5–S14. 127. Andersen AE, Ryan GL. Eating disorders in the obstetric and gynecologic patient population. Obstet Gynecol 2009;114:1353–1367. 128. Schardein JL. Congenital abnormalities and hormones during pregnancy: a clinical review. Teratology 1980;22:251–270. 129. Resseguie LJ, Hick JF, Bruen JA, et al. Congenital malformations among offspring exposed in utero to progestins, Olmsted County, Minnesota, 1936–1974. Fertil Steril 1985;43:514–519. 130. Rebar RW. Premature ovarian failure. Obstet Gynecol 2009; 113:1355–1363. 131.


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Gynecology_Novak. 130. Rebar RW. Premature ovarian failure. Obstet Gynecol 2009; 113:1355–1363. 131. North American Menopause Society. Estrogen and progestogen use in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause 2010;17:242– 255. 132. Cusan L, Dupont A, Gomez JL, et al. Comparison of ﬂutamide and spironolactone in the treatment of hirsutism: a randomized controlled trial. Fertil Steril 1994;61:281–287. 133. Belisle S, Love EJ. Clinical efficacy and safety of cyproterone acetate in severe hirsutism: results of a multicentered Canadian study. Fertil Steril 1986;46:1015–1020. 134. Rittmaster RS. Finasteride. N Engl J Med 1994;330:120–125. 135. Price TM. Finasteride for hirsutism: there’s new approach to treating hirsutism—but is it any better or even as effective as conventional therapy? Contemp Obstet Gynecol 1999;44:73–84. 136.


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Gynecology_Novak. 135. Price TM. Finasteride for hirsutism: there’s new approach to treating hirsutism—but is it any better or even as effective as conventional therapy? Contemp Obstet Gynecol 1999;44:73–84. 136. van Santbrink EJP, Eijkemans MJ, Laven JSE, et al. Patient-tailored conventional ovulation induction algorithms in anovulatory infertility. Trend Endocrinol Metabol 2005;16:381–389. 137. Whittemore AS, Harris R, Itnyre J, et al. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. Am J Epidemiol 1992;136:1184–1203. 138. Rossing MA, Daling JR, Weiss NL, et al. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994;331:771–776. 139. Venn A, Watson L, Lumley J, et al. Breast and ovarian cancer incidence after infertility and in vitro fertilization. Lancet 1995;346:995– 1000. 140.


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Gynecology_Novak. 139. Venn A, Watson L, Lumley J, et al. Breast and ovarian cancer incidence after infertility and in vitro fertilization. Lancet 1995;346:995– 1000. 140. Mosgaard BJ, Lidegaard O, Kjaer SK, et al. Infertility, fertility drugs, and invasive ovarian cancer: a case control study. Fertil Steril 1997;67:1005–1012. 141. Brinton LA, Moghissi K, Scoccia B. Ovulation induction and cancer risk. Fertil Steril 2005;83:261–274. 142. Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in women. Fertil Steril 2006;86:S187–S193. 143. McClamrock HD, Adashi EY. Ovulation induction. I. Appropriate use of clomiphene citrate. Female Patient 1988;13:92–106. 144. Rust LA, Israel R, Mishell DR Jr. An individualized graduated therapeutic regimen for clomiphene citrate. Am J Obstet Gynecol 1974;120:785–790. 145.


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Gynecology_Novak. 144. Rust LA, Israel R, Mishell DR Jr. An individualized graduated therapeutic regimen for clomiphene citrate. Am J Obstet Gynecol 1974;120:785–790. 145. Lobo RA, Granger LR, Davajan V, et al. An extended regimen of clomiphene citrate in women unresponsive to standard therapy. Fertil Steril 1982;37:762–766. 146. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–566. 147. Creanga AA, Bradley HM, McCormick C, et al. Use of metformin in polycystic ovary syndrome: a meta-analysis. Obstet Gynecol 2008;111:959–968. 148. Polyzos NP, Tzioras S, Badawy AM, et al. Aromatase inhibitors for female infertility: a systematic review of the literature. Reprod Biomed Online 2009;19:456–471. 149. Mamas L, Mamas E. Premature ovarian failure and dehydroepiandrosterone. Curr Opin Obstet Gynecol 2009;21:306–308. 150.


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Gynecology_Novak. 149. Mamas L, Mamas E. Premature ovarian failure and dehydroepiandrosterone. Curr Opin Obstet Gynecol 2009;21:306–308. 150. Noyes N, Porcu E, Borini A. Over 900 oocyte cryopreservation babies born with no apparent increase in congenital anomalies. Reprod Biomed Online 2009;18:769–776. 151. Oktay K, Oktem O. Ovarian cryopreservation and transplantation for fertility preservation for medical indications: report of an ongoing experience. Fertil Steril 2010;93:762–768. 152. Boissonnas CC, Davy C, Bornes M, et al. Careful cardiovascular screening and follow-up of women with Turner syndrome before and during pregnancy is necessary to prevent maternal mortality. Fertil Steril 2009;91:929.e5–e7. 153. Bondy C, Rosing D, Reindollar R. Cardiovascular risks of pregnancy in women with Turner syndrome. Fertil Steril 2009;91: e31–e32. C. Matthew Peterson


Gynecology_Novak

Gynecology_Novak. 153. Bondy C, Rosing D, Reindollar R. Cardiovascular risks of pregnancy in women with Turner syndrome. Fertil Steril 2009;91: e31–e32. C. Matthew Peterson Hyperandrogenism most often presents as hirsutism, which usually arises as a result of androgen excess related to abnormalities of function in the ovary or adrenal glands. By contrast, virilization is rare and indicates marked elevation in androgen levels. The most common cause of hyperandrogenism and hirsutism is polycystic ovarian syndrome (PCOS). There are only two major criteria for the diagnosis of PCOS: anovulation and the presence of hyperandrogenism as established by clinical or laboratory means. Patients with PCOS frequently exhibit insulin resistance and hyperinsulinemia. Combination oral contraceptives (OCs) decrease adrenal and ovarian androgen production and reduce hair growth in nearly two-thirds of hirsute patients.


Gynecology_Novak

Gynecology_Novak. Combination oral contraceptives (OCs) decrease adrenal and ovarian androgen production and reduce hair growth in nearly two-thirds of hirsute patients. Because hyperinsulinemia appears to play a role in PCOS-associated anovulation, treatment with insulin sensitizers may shift the endocrine balance toward ovulation and pregnancy, either alone or in combination with other treatment modalities. Excluding cases that are of iatrogenic or factitious etiology, adrenocorticotropic hormone–independent forms of Cushing syndrome are adrenal in origin. Adrenal tumors are usually very large by the time Cushing syndrome is manifest. Congenital adrenal hyperplasia is transmitted as an autosomal recessive disorder. Deficiency of 21-hydroxylase is responsible for more than 90% of cases of adrenal hyperplasia resulting from an adrenal enzyme deficiency.


Gynecology_Novak

Gynecology_Novak. Patients with severe hirsutism, virilization, or recent and rapidly progressing signs of androgen excess require careful investigation for the presence of an androgen-secreting neoplasm. Ovarian neoplasms are the most frequent androgen-producing tumors. Elevations in prolactin may cause amenorrhea or galactorrhea. Amenorrhea without galactorrhea is associated with hyperprolactinemia in approximately 15% of women. In patients with both galactorrhea and amenorrhea, approximately two-thirds will have hyperprolactinemia; of those, approximately one-third will have a pituitary adenoma. In more than one-third of women with hyperprolactinemia, a radiologic abnormality consistent with a microadenoma (>1 cm) is found.


Gynecology_Novak

Gynecology_Novak. ● Because levels of thyroid-stimulating hormone (TSH) are sensitive to excessive or deficient levels of circulating thyroid hormone, and because most disorders of hyperthyroidism and hypothyroidism are related to dysfunction of the thyroid gland, TSH levels are used to screen for these disorders. The most common thyroid abnormalities in women, autoimmune thyroid disorders, represent the combined effects of the multiple antibodies produced. Severe primary hypothyroidism is associated with amenorrhea or anovulation. The classic triad of exophthalmos, goiter, and hyperthyroidism in Graves disease is associated with symptoms of hyperthyroidism.


Gynecology_Novak

Gynecology_Novak. The endocrine disorders encountered most frequently in gynecologic patients are those related to disturbances in the regular occurrence of ovulation and accompanying menstruation. The most prevalent are those characterized by androgen excess, often with insulin resistance, including what is arguably the most common endocrinopathy in women— polycystic ovary syndrome (PCOS). Other conditions leading to ovulatory dysfunction, hirsutism, or virilization, and common disorders of the pituitary and thyroid glands associated with reproductive abnormalities, are reviewed in this chapter.


Gynecology_Novak

Gynecology_Novak. Hyperandrogenism most often presents as hirsutism, which arises as a result of androgen excess related to abnormalities of function in the ovary or adrenal glands, constitutive increase in expression of androgen effects at the level of the pilosebaceous unit, or a combination of the two. By contrast, virilization is rare and indicates marked elevations in androgen levels. An ovarian or adrenal neoplasm that may be benign or malignant commonly causes virilization.


Gynecology_Novak

Gynecology_Novak. Hirsutism Hirsutism, the most frequent manifestation of androgen excess in women, is defined as excessive growth of terminal hair in a male distribution. This refers particularly to midline hair, side burns, moustache, beard, chest or intermammary hair, and inner thigh and midline lower back hair entering the intergluteal area. The response of the pilosebaceous unit to androgens in these androgen responsive areas transforms vellus hair (fine, nonpigmented, short) that is normally present into terminal hair (coarse, stiff, pigmented, and long).


Gynecology_Novak

Gynecology_Novak. Androgen effects on hair vary in relation to specific regions of the body surface. Hair that shows no androgen dependence includes lanugo, eyebrows, and eyelashes. The hair of the limbs and portions of the trunk exhibits minimal sensitivity to androgens. Pilosebaceous units of the axilla and pubic region are sensitive to low levels of androgens, such that the modest androgenic effects of adult levels of androgens of adrenal origin are sufficient for substantial expression of terminal hair in these areas. Follicles in the distribution associated with male patterns of facial and body hair (midline, facial, inframammary) require higher levels of androgens, as seen with normal testicular function or abnormal ovarian or adrenal androgen production. Scalp hair is inhibited by gonadal androgens, in varying degrees, as determined by age and genetic determination of follicular responsiveness, resulting in the common frontal-parietal balding seen in some males and in virilized females.


Gynecology_Novak

Gynecology_Novak. in varying degrees, as determined by age and genetic determination of follicular responsiveness, resulting in the common frontal-parietal balding seen in some males and in virilized females. Hirsutism results from both increased androgen production and skin sensitivity to androgens. Skin sensitivity depends on the genetically determined local activity of 5α-reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT), the bioactive androgen in hair follicles.


Gynecology_Novak

Gynecology_Novak. Hair demonstrates cyclic activity between growth (anagen), involution (catagen), and resting (telogen) phases. The durations of both the growth and resting phases vary according to region of the body, genetic factors, age, and hormonal effects. The cycles of growth, rest, and shedding are normally asynchronous, but when synchronous entry into telogen phase is triggered by major metabolic or endocrine events, such as pregnancy and delivery, or severe illness, dramatic (although transient) hair loss may occur in the following months (telogen efﬂuvium).


Gynecology_Novak

Gynecology_Novak. Hirsutism is a relative, rather than absolute, designation. What is normal in one setting may be considered abnormal in others; social and clinical reactions to hirsutism can vary significantly, reﬂecting ethnic variation in skin sensitivity to androgens and cultural ideals. Androgen-dependent hair (excluding pubic and axillary hair) occurs in only 5% of premenopausal white women and is considered abnormal by white women of North America, whereas considerable facial and male pattern hair in other areas may be more common and more often considered acceptable and normal among such groups as the Inuit and women of Mediterranean background.


Gynecology_Novak

Gynecology_Novak. Two conditions should be distinguished from hirsutism. Hypertrichosis is the term reserved for androgen-independent terminal hair in nonsexual areas, such as the trunk and extremities. This may be the result of an autosomal-dominant congenital disorder, a metabolic disorder (such as anorexia nervosa, hyperthyroidism, porphyria cutanea tarda), or medications (e.g., acetazolamide, anabolic steroids, androgenic progestins, androgens, cyclosporine, diazoxide, dehydroepiandrosterone (DHEA), heavy metals, interferon, methyldopa, minoxidil, penicillamine, phenothiazines, phenytoin, streptomycin, reserpine, valproic acid). Virilization is a marked and global masculine transformation that includes coarsening of the voice, increase in muscle mass, clitoromegaly (normal clitoral dimensions ± standard deviation [SD] are 3.4 + 1 mm width by 5.1 + 1.4 mm length) and features of defeminization (loss of breast volume and body fat contributing to feminine body contour) (1). Although hirsutism


Gynecology_Novak

Gynecology_Novak. standard deviation [SD] are 3.4 + 1 mm width by 5.1 + 1.4 mm length) and features of defeminization (loss of breast volume and body fat contributing to feminine body contour) (1). Although hirsutism accompanies virilization, the presence of virilization indicates a high likelihood of more serious conditions than are common with hirsutism alone and should prompt evaluation to exclude ovarian or adrenal neoplasm. Although rare, these diagnoses become likely when onset of androgen effects is rapid or sufficiently pronounced to produce the picture of virilization.


Gynecology_Novak

Gynecology_Novak. The history should focus on the age of onset and rate of progression of hirsutism or virilization. A rapid rate of progression or virilization is associated with a more severe degree of hyperandrogenism and should raise suspicion of ovarian and adrenal neoplasms or Cushing syndrome. This is true whether rapid progression or virilization occurs before, during, or after puberty. Anovulation, manifesting as amenorrhea or oligomenorrhea, increases the probability that there is underlying hyperandrogenism. Hirsutism occurring with regular cycles is more commonly associated with normal androgen levels and thus is attributed to increased genetic sensitivity of the pilosebaceous unit and is termed idiopathic hirsutism. When virilization is present, anovulation virtually always occurs.


Gynecology_Novak

Gynecology_Novak. In determining the extent of hirsutism, a sensitive and tactful approach by the physician is mandatory and should include questions regarding the use and frequency of shaving and/or chemical or mechanical depilatories. Typically, clinical evaluation of the degree of hirsutism is subjective. Most physicians arbitrarily classify the degree of hirsutism as mild, moderate, or severe. Objective assessment is helpful, especially in establishing a baseline from which therapy can be evaluated. The Ferriman–Gallwey Scoring System for Hirsutism quantitates the extent of hair growth in the most androgen sensitive sites. It is a scoring scale of androgen-sensitive hair in nine body areas rated on a scale of 0 to 4 (2). A total score higher than 8 is defined as hirsutism (Fig. 31.1) (3). Although widely used, this scoring system has limitations, one of which is the fact that the scale does not include the sideburn, buttocks, and perineal areas. Substantial hirsutism may be confined to one or two


Gynecology_Novak

Gynecology_Novak. used, this scoring system has limitations, one of which is the fact that the scale does not include the sideburn, buttocks, and perineal areas. Substantial hirsutism may be confined to one or two areas without exceeding the cutoff value in total hirsutism score. The score does not reﬂect the extent to which hirsutism affects a woman’s well being (3,4).


Gynecology_Novak

Gynecology_Novak. A family history should be obtained to disclose evidence of idiopathic hirsutism, PCOS, congenital or adult onset adrenal hyperplasia (CAH or AOAH), diabetes mellitus, and cardiovascular disease. A history of drug use should be obtained. In addition to drugs that commonly cause hypertrichosis, anabolic steroids and testosterone derivatives may cause hirsutism and even virilization. During the physical examination, attention should be directed to obesity, hypertension, galactorrhea, male-pattern baldness, acne (face and back), and hyperpigmentation. With virilization, the presence of an androgen-producing ovarian neoplasm or Cushing syndrome must be considered. In many cases of Cushing syndrome, the patient’s presenting symptom is hirsutism. This devastating disorder may masquerade as other disorders such as AOAH and PCOS. Before making these diagnoses, the physician should search for the physical signs of the syndrome such as “moon face,” plethora, purple striae, dorsocervical and


Gynecology_Novak

Gynecology_Novak. disorders such as AOAH and PCOS. Before making these diagnoses, the physician should search for the physical signs of the syndrome such as “moon face,” plethora, purple striae, dorsocervical and supraclavicular fat pads, and proximal muscle weakness. A moon-shaped face, upper body obesity, muscle weakness, and the development of a pad of fat between the shoulder blades are particularly notable to both patients and diagnosticians considering the diagnosis of Cushing syndrome.


Gynecology_Novak

Gynecology_Novak. Figure 31.1 Ferriman-Gallwey hirsutism scoring system. Each of the nine body areas most sensitive to androgen is assigned a score from 0 (no hair) to 4 (frankly virile), and these separate scores are summed to provide a hormonal hirsutism score. (Reproduced from Hatch R, Rosefield RL, Kim MH, et al. Hirsutism: implications, etiology, and management. Am J Obstet Gynecol 1981;140:815–830. c Elsevier.) and luteinizing hormone (LH), respectively (Fig. 31.2). Biosynthesis begins with the rate-limiting conversion of cholesterol to pregnenolone by side-chain cleavage enzyme. Thereafter, pregnenolone undergoes a two-step conversion to the 17-ketosteroid DHEA along the -5 steroid pathway. This conversion is accomplished by CYP17, an enzyme with both 17αhydroxylase and 17,20-lyase activities. In a parallel fashion, progesterone undergoes transformation to androstenedione in the -4 steroid pathway. The metabolism of -5 to -4 intermediates is accomplished via a -5-isomerase, 3β-hydroxysteroid


Gynecology_Novak

Gynecology_Novak. a parallel fashion, progesterone undergoes transformation to androstenedione in the -4 steroid pathway. The metabolism of -5 to -4 intermediates is accomplished via a -5-isomerase, 3β-hydroxysteroid dehydrogenase (3β-HSD).


Gynecology_Novak

Gynecology_Novak. Secretion of adrenal 17-ketosteroids increases prepubertally and independently of pubertal maturation of the hypothalamic–pituitary–ovarian axis. This alteration in adrenal steroid secretion is termed adrenarche and is characterized by a dramatic change in the response of the adrenal cortex to ACTH and with preferential secretion of -5 steroids, including 17hydroxypronenolone, DHEA, and dehydroepiandrosterone sulfate (DHEAS). The basis for this action is related to the increase in the zona reticularis and in the increased activity of the 17hydroxylase and the 17,20-lyase enzymes. Independent of the increase in ovarian androgen secretion accompanying puberty, the increase in adrenal androgens owing to adrenarche can account for significant increases in pubic and axillary hair and sweat production by the axillary pilosebaceous units.


Gynecology_Novak

Gynecology_Novak. Approximately half of a woman’s serum testosterone is derived from peripheral conversion of secreted androstenedione and the other half is derived from direct glandular (ovarian and adrenal) secretion. The ovaries and adrenal glands contribute almost equally to testosterone production in women. The contribution of the adrenals is achieved primarily through secretion of androstenedione. Figure 31.2 Major steroid biosynthesis pathway. Laboratory Assessment of Hyperandrogenemia Approximately 66% to 78% of circulatory testosterone is bound to sex hormone–binding globulin (SHBG) and is considered biologically inactive. Most of the proportion of serum testosterone that is not bound to SHBG is weakly associated with albumin (20% to 32%). A small percentage (1% to 2%) of testosterone is entirely unbound or free. The fraction of circulating testosterone that is unbound by SHBG has an inverse relationship with the SHBG concentration.


Gynecology_Novak

Gynecology_Novak. Increased SHBG levels are noted in conditions associated with high estrogen levels. Pregnancy, the luteal phase, use of estrogen (including oral contraceptives), and conditions causing elevated thyroid hormone levels and cirrhosis of the liver are associated with reduced fractions of free testosterone caused by elevated SHBG levels. Conversely, levels of SHBG decrease and result in elevated free testosterone fractions in response to androgens, androgenic disorders (PCOS, adrenal hyperplasia or neoplasm, Cushing syndrome), androgenic medications (i.e., progestational agents with androgenic biologic activities, such as danazol, glucocorticoids, and growth hormones), hyperinsulinemia, obesity, and prolactin.


Gynecology_Novak

Gynecology_Novak. In hyperandrogenic states, increases in testosterone production are not proportionately reﬂected in increased total testosterone levels because of the depression of SHBG levels that occurs concomitant with increasing androgen effects on the liver. Therefore, when moderate hyperandrogenism, characteristic of many functional hyperandrogenic states, occurs, elevations in total testosterone levels may remain within the normal range, and only free testosterone levels will reveal the hyperandrogenism. Severe hyperandrogenism, as occurs in virilization and that results from neoplastic production of testosterone, is reliably detected by measures of total testosterone. Therefore, in practical clinical evaluation of the hyperandrogenic patient, determination of the total testosterone level in concert with clinical assessment is frequently sufficient for diagnosis and management. When more precise delineation of the degree of hyperandrogenism is desired, measurement or estimation of free


Gynecology_Novak

Gynecology_Novak. concert with clinical assessment is frequently sufficient for diagnosis and management. When more precise delineation of the degree of hyperandrogenism is desired, measurement or estimation of free testosterone levels can be undertaken and will more reliably reﬂect increases in testosterone production. These measurements are not necessary in evaluating the majority of patients, but they are common in clinical research studies and may be useful in some clinical settings. Because many practitioners measure some form of testosterone level, they should understand the methods used and their accuracy. Although equilibrium dialysis is the gold standard for measuring free testosterone, it is expensive, complex, and usually limited to research settings. In a clinical setting, free testosterone levels can be estimated by assessment of testosterone binding to albumin and SHBG.


Gynecology_Novak

Gynecology_Novak. Testosterone, that is nonspecifically bound to albumin (AT), is linearly related to free testosterone (FT) by the equation: AT = Ka [A] × FT, where AT is the albumin-bound testosterone, Ka is the association constant of albumin for testosterone, and [A] is the albumin concentration. In many cases of hirsutism, albumin levels are within a narrow physiologic range and thus do not significantly affect the free testosterone concentration. When physiologic albumin levels are present, the free testosterone level can be estimated by measuring the total testosterone and SHBG. In individuals with normal albumin levels, this method has reliable results compared with those of equilibrium dialysis. It provides a rapid, simple, and accurate determination of the total and calculated free testosterone level and the concentration of SHBG.


Gynecology_Novak

Gynecology_Novak. The bioavailable testosterone level is based on the relationship of albumin and free testosterone and incorporates the actual albumin level with the total testosterone and SHBG. This combination of total testosterone, SHBG, and albumin level measurements can be applied to derive a more accurate estimate of available bioactive testosterone and thus the androgen effect derived from testosterone. Bioactive testosterone determined in this manner provides a superior estimate of the effective androgen effect derived from testosterone (5).


Gynecology_Novak

Gynecology_Novak. Pregnancy can alter the accuracy of measurements of bioavailable testosterone. During pregnancy, estradiol, which shares with testosterone a high affinity for SHBG, occupies a large proportion of SHBG binding sites, so that measurement of SHBG levels can overestimate the binding capacity of SHBG for testosterone. Derived estimates of free testosterone, as opposed to direct measure by equilibrium dialysis, are therefore inaccurate during pregnancy. Testosterone measurements in pregnancy are primarily of interest when autonomous secretion by tumor or luteoma is in question, and for these, total testosterone determinations provide sufficient information for diagnosis.


Gynecology_Novak

Gynecology_Novak. For testosterone to exert its biologic effects on target tissues, it must be converted into its active metabolite, DHT, by 5α-reductase (a cytosolic enzyme that reduces testosterone and androstenedione). Two isozymes of 5α-reductase exist: type 1, which predominates in the skin, and type 2, or acidic 5α-reductase, which is found in the liver, prostate, seminal vesicles, and genital skin. The type 2 isozyme has a 20-fold higher affinity for testosterone than type 1. Both type 1 and 2 deficiencies in males result in ambiguous genitalia, and both isozymes may play a role in androgen effects on hair growth. Dihydrotestosterone is more potent than testosterone, primarily because of its higher affinity and slower dissociation from the androgen receptor. Although DHT is the key intracellular mediator of most androgen effects, measurements of circulating levels are not clinically useful. The relative androgenicity of androgens is as follows: DHEAS = 5.


Gynecology_Novak

Gynecology_Novak. The relative androgenicity of androgens is as follows: DHEAS = 5. Until adrenarche, androgen levels remain low. Around 8 years of age, adrenarche is heralded by a marked increase in DHEA and DHEAS. The half-life of free DHEA is extremely short (about 30 minutes) but extends to several hours if DHEA is sulfated. Although no clear role is identified for DHEAS, it is associated with stress and levels decline steadily throughout adult life. After menopause, ovarian estrogen secretion ceases, and DHEAS levels continue to decline, whereas testosterone levels are maintained or may even increase. Although postmenopausal ovarian steroidogenesis contributes to testosterone production, testosterone levels retain diurnal variation, reﬂecting an ongoing and important adrenal contribution. Peripheral aromatization of androgens to estrogens increases with age, but because small fractions (2% to 10%) of androgens are metabolized in this fashion, such conversion is rarely of clinical significance.


Gynecology_Novak

Gynecology_Novak. Laboratory Evaluation The 2008 Endocrine Society Clinical Practice Guidelines suggest testing for elevated androgen levels in women with moderate (Ferriman–Gallwey hirsutism score 9 or greater) or severe hirsutism or hirsutism of any degree when it is sudden in onset, rapidly progressive, or associated with other abnormalities such as menstrual dysfunction, infertility, significant acne, obesity, or clitoromegaly. These guidelines suggest against testing for elevated androgen levels in women with isolated mild hirsutism because the likelihood of identifying a medical disorder that would change management or outcome is extremely low (Fig. 31.3) (4). Medications that cause hirsutism are listed and should be considered (Table 31.1).