Can Underactive Thyroid Cause Oligoovulation

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Ovarian failure

Congenital absence of the uterus and vagina GnRH deficiency Constitutional delay of puberty

Frequency

Adapted from: Timmreck LS, Reindollar RH. Contemporary issues in primary amenorrhea. Obstet Gynecol Clin North Am 2003; 30:287-302.

Hypogonadism, Uterus Present

Patients with a uterus without any evidence of prior estrogen exposure (Fig. 3.5) require a work up similar to those patients with evidence of prior estrogen exposure (Fig. 3.3). However, since they are presenting with primary amenorrhea, several additional diagnoses, discussed in the next section, need to be considered.

Diagnoses

To summarize, the evaluation of primary or secondary amenorrhea leads to a differential diagnosis that includes both eugonadal and hypogonadal states. Hypogonadism can be further classified by FSH levels: hypogonadotropic (low FSH) and hypergonadotropic (high FSH) hypogonadism. Tables 3.3 and 3.4 summarize common causes of both primary and secondary amenorrhea.

Eugonadotropic Amenorrhea (Normal FSH and LH)

Eugonadal amenorrhea covers a spectrum of disorders ranging from common to extremely rare conditions. Polycystic ovary syndrome (PCOS), a very common gynecologic condition, can lead to both primary and secondary amenorrhea. It is characterized by oligo-ovulation or anovulation, clinical or biochemical evidence of

Table 3.4. Causes of secondary amenorrhea

Cause

Frequency

Anovulation

28%

Ovarian Failure - abnormal karyotype

0.5%

- normal karyotype

10%

Hypothalamic suppression

10%

Weight loss/anorexia

10%

Prolactinoma

7.5%

Asherman's syndrome

7%

Hypothyroidism

1%

Adapted from: Reindollar RH, Novak M, Tho SP et al. Adult-onset amenorrhea: A study of 262 patients. Am J Obstet Gynecol 1986; 155:531-543.

Adapted from: Reindollar RH, Novak M, Tho SP et al. Adult-onset amenorrhea: A study of 262 patients. Am J Obstet Gynecol 1986; 155:531-543.

Environmental Causes Amenorrhea
Figure 3.5. Hypogonadism with a uterus.

hyperandrogenemia, and polycystic appearing ovaries. According to the 2003 Rotterdam criteria, two out of three of these features must be present for this diagnosis. In addition to amenorrhea, patients with PCOS frequently have problems with infertility and insulin resistance. They are also at increased risk for developing metabolic syndrome, endometrial hyperplasia and endometrial cancer.

In addition to PCOS, several anatomic abnormalities can result in amenorrhea in the presence of normal estradiol levels. Congenital absence of the uterus and vagina, also known as Mayer-Rokitansky-Kuster-Hauser syndrome, is an example of eugonadal amenorrhea. Failure of the undifferentiated mullerian system to fuse properly results in varying degrees of uterine and vaginal agenesis in these women. Patients often have a short vaginal pouch or absent vagina. The uterus and fallopian tubes are frequently absent or if present consist of small uterine remnants attached to normal fallopian tubes and ovaries. Thirty percent of these patients have renal anomalies such as unilateral renal agenesis and twelve percent have skeletal anomalies. Because ovarian function is normal, ovarian steroidogenesis is intact, puberty is normal, but menstruation fails to occur. Other less common congenital anomalies resulting in amenorrhea include: absence of the endometrial cavity or endometrium, cervical atresia, transverse vaginal septum and imperforate hymen. Absence of the endometrium is exceedingly rare. Cervical atresia may present as hematometria or hematoperitoneum. Patients with transverse septae, resulting from failure of the lower third of the vagina to canalize, may present with hematocolpos and urinary frequency. A vaginal septum may be associated with abnormalities of the fallopian tubes or unilateral absence of the ovary and fallopian tube. Imperforate hymen may be distinguished from a transverse vaginal septum by physical examination. Patients with an imperforate hymen will demonstrate distention of the introitus by the he-matocolpos when they perform a valsalva maneuver. Asherman's syndrome, an acquired cause of amenorrhea, results from partial or complete destruction of the endometrium, often as a complication of a surgical procedure. Asherman's syndrome, or uterine synechiae, may result from overzealous postpartum curettage, uterine surgery (cesarean section, metroplasty or myomectomy), uterine artery emboliza-tion, and infection. Rare infectious causes ofAsherman's syndrome include tuberculosis and uterine schistosomiasis.

Various types of male pseudo-hermaphrodism can cause primary amenorrhea. The most common of these conditions, androgen insensitivity syndrome (AIS) occurs when an abnormal androgen receptor fails to initiate a signal in response to testosterone due to mutations in either the androgen binding or DNA binding sites. In its classical form, patients have a 46 XY karyotype and testes which produce both testosterone and Mullerian inhibitory substance (MIS). MIS causes regression of the Mullerian system and the absence of internal female genitalia. These individuals are unable to respond to testosterone with masculinization of the external genitalia and the default, an external female phenotype and formation of a short vaginal pouch, is seen in these patients. At puberty, peripheral aromatase converts testosterone to estra-diol and breast development ensues. These patients also have very little pubic hair and are usually tall due to the presence of the Y chromosome. Partially descended testicles may result in the finding of bilateral inguinal hernias in childhood. In addition to the classical form of AIS, incomplete androgen insensitivity may present with amenorrhea; however, these phenotypic females may undergo varying degrees of virilization with puberty. Another form of male pseudo-hermaphrodism is caused by a deficiency in 17-ketoreductase. Instead of a defect in the androgen receptor, these patients have impaired testosterone production and present with clinical findings that are similar to incomplete androgen insensitivity.

Hypogonadism comprises the remainder of the causes of amenorrhea. Hypogo-nadism may result when defects occur at the level of the hypothalamus and pituitary or at the level of the ovary. Evaluation of gonadotropin levels can readily distinguish between the two. Hypogonadotropic hypogonadism represents a central nervous system abnormality and hypergonadotropic hypogonadism is indicative of a process occurring in the ovary. The first of these, hypogonadotropic hypogonadism, may be subdivided into the following categories: congenital abnormalities, acquired lesions, endocrinopathies, systemic illnesses, maladaptive behaviors, constitutional delay of puberty, and idiopathic hypothalamic hypogonadism.

Hypogonadotropic Amenorrhea

The most common congenital cause of hypogonadotropic hypogonadism is Kallmann syndrome. Kallmann syndrome is characterized by isolated GnRH deficiency resulting in primary amenorrhea and sexual infantilism. Patients also have anosmia or hyposmia, midline facial defects and occasionally renal agenesis. Consistent with hyposmia/anosmia, imaging studies demonstrate absent or hypoplastic olfactory bulbs. It may be inherited in a X-linked and autosomal dominant or recessive fashion. The X-linked recessive gene (KAL gene) encodes for an adhesion protein. Lack of this protein prevents GnRH producing neurons from migrating to their normal position in the hypothalamus adjacent to the anterior pituitary. Other conditions leading to hypogonadotropic amenorrhea include: autosomal recessive GnRH receptor mutations, X-linked adrenal hypoplasia, mutations in the FSH p gene, and Prader-Willi and Laurence-Moon-Biedl syndromes.

Acquired lesions in the CNS may also result in amenorrhea. Malignant and nonneoplastic intrasellar masses, such as nonfunctioning pituitary adenomas, cran-iopharyngiomas, cysts, fat deposits, tuberculosis, and sarcoidosis can lead to pituitary compression and hypogonadotropic amenorrhea. Nonfunctioning pituitary tumors comprise approximately 30-40% of all pituitary adenomas and may secrete biologically inactive FSH, a subunit, and rarely LH. Craniopharyngiomas usually develop between ages 6 to 14 years. These calcified-appearing tumors on radiological imaging may invade and destroy the pituitary and suprasellar regions. Lesions such as internal carotid aneurysms and obstruction of the aqueduct of Sylvius may produce hypogonadotropic amenorrhea. Other pituitary tumors may lead to endo-crinopathies that secondarily lead to amenorrhea. Over 50% of pituitary tumors detected at autopsy secrete prolactin, which can inhibit pulsatile secretion of GnRH. Prolactinomas typically develop after puberty has started. Increased ovarian estrogen production leads to increased prolactin production via increased mRNA. About one third of patients with a prolactinoma present clinically with galactorrhea. Other endocrine tumors, such as Cushing's syndrome and acromegaly usually produce amenorrhea prior to their full clinical expression. Deficiencies in hormones may also produce or accompany hypogonadotropic amenorrhea. Hypothyroidism is responsible for a small fraction of patients with amenorrhea, but is readily treatable and normal menstruation is quickly restored. Sheehan's syndrome, pituitary insufficiency due to ischemia or infarction after an obstetric hemorrhage, is characterized by pan-hypopituitarism resulting in amenorrhea among other problems.

In addition to congenital and acquired lesions of the CNS, all manners of stress may affect the hypothalamus and result in hypogonadotropic amenorrhea. Systemic illness such as poorly controlled diabetes, childhood rheumatoid arthritis and malabsorptive bowel disease may affect gonadotropin production and result in delayed menarche. Starvation as seen in eating disorders is a profound stress to the body. Anorexia nervosa usually presents after menarche and represents a significant life-threatening condition that may initially be noticed secondary to amenorrhea. Neuropeptide Y, a peptide produced in the arcuate nucleus, normally stimulates feeding behavior; however, when elevated in anorexia nervosa, it inhibits GnRH secretion. Weight gain restores gonadotropin production, but normal menses do not always ensue. Similar to anorexia, extreme exercise especially prior to menarche may delay puberty. A reduction in body fat below a critical level and an increase in energy expenditure trigger a decrease in leptin levels. Lower leptin levels can suppress reproductive and thyroid functions and increase adrenal activity. Both patients with anorexia and exercise-induced amenorrhea have low FSH/LH and elevated cortisol and may be difficult to distinguish clinically. However, they differ subtly in other endocrine markers. Patients with anorexia have normal TSH and thyroxine (T4), but low T3 and elevated reverse T3; whereas, patients with exercise-induced amenorrhea have reductions in all thyroid hormones (T4, T3, rT3) and elevated growth hormone, testosterone, prolactin and endorphins.

Another potential cause of delayed menarche associated with decreased FSH is constitutional delay of puberty. These girls usually present from families with similar histories of delayed menarche. They are shorter than their peers, and bone age lags behind their chronological age. If given GnRH, they will respond with a pubertal pattern of gonadotropin release (LH>FSH). When their bone age reaches 9 to 11 years, they usually spontaneously enter puberty.

When all other identifiable causes of hypogonadotropic amenorrhea are ruled out, the remaining patients with low or normal gonadotropin levels, normal prolac-tin, and normal imaging studies are labeled as having idiopathic hypothalamic amen-orrhea. However, many of these will have increased cortisol secretion and may represent another class of stress-induced amenorrhea.

Hypergonadotropic Amenorrhea

In contrast to hypogonadotropic hypogonadism, hypergonadotropic hypogo-nadism is often the result of primary ovarian hypofunction. Hypergonadotropic amenorrhea includes a variety of clinical entities including: Turner's syndrome, ovarian failure, and pseudo-ovarian failure.

Turner's syndrome results from a missing sex chromosome in all or a portion of the cells. The resulting karyotype, 45 X, indicates they have a single copy of an X chromosome (monosomy X). Absence of key ovarian genes on the other X chromosome results in premature loss of germ cells. During fetal life, Turner's syndrome patients have a normal number of germ cells at midgestation; however, an accelerated loss of germ cells occurs thereafter. Due to this accelerated loss of follicles, less than 15% of women with Turner's syndrome will enter spontaneous puberty. Furthermore, less than 5% will achieve a spontaneous pregnancy before developing ovarian failure. Mosaicism, in which all of the cell lines are not monosomy X, explains why some patients are able to initiate puberty and even achieve pregnancy. Approximately 5% of Turner's syndrome patients have Y chromosome material that is evident on karyotyping. This number doubles when specific Y chromosome DNA probes are used in the evaluation. However, only mosaic Turner's syndrome patients with the presence of a Y cell line on karyotype are at increased risk for gonadoblastoma.

In addition to premature ovarian failure, other stigmata of Turner's syndrome may be observed which include: cardiovascular abnormalities that may cause complications in pregnancy; wide spaced nipples (shield chest); renal anomalies (horseshoe kidney); high arched palate; low hairline; webbed neck; multiple pigmented nevi; short fourth metacarpal digits; increased carrying angle of the arms; lymphedema; and short stature with height usually less than 63 inches/160 cm. Turner's syndrome patients also have an increased prevalence of autoimmune disorders—Hashimoto's thyroiditis and diabetes mellitus.

Hypergonadotropic patients with a normal complement of chromosomes may develop amenorrhea secondary to, or as a transition to ovarian failure. Multiple causes of 46 XX ovarian failure have been elucidated. Acquired causes include: radiation; chemotherapy; and possibly infectious elements like childhood viruses. Autoimmune ovarian failure has been commonly described. Therefore, a careful look for other autoimmune disorders is imperative. Other autoimmune disorders include: Hashimoto's thyroiditis; pernicious anemia; vitiligo; diabetes mellitus; hypoparathy-roidism; and, importantly, adrenal insufficiency. Adrenal insufficiency is a potentially lethal condition that may present with subtle findings of hyperpigmentation, weakness, lethargy, anorexia, nausea, vomiting, and orthostatic hypotension. Genetic causes of ovarian failure include: mutations occurring in the POF1 and 2 regions of the X chromosome; expansion of CGG repeats between 55-200 in the FMR1 gene as seen in the Fragile X syndrome premutation; blepharosphimosis/ ptosis/epicanthus inversus syndrome; ataxia telangectasia; myotonic dystrophy; and galactosemia. Patients with 46 XY gonadal dysgenesis (Swyer syndrome) also have a normal, though unexpected, complement of chromosomes. They have mutations in or in proximity to the SRY gene that results in impaired testicular development. Streak gonads rather than normal testes form, MIS is not produced and normal internal female genitalia develop. In the absence of normal testosterone production, normal external female genitalia also develop. Because gonadal steroidogenesis is not normal, puberty and menses do not occur. The presence of a Y chromosome also places these patients at increased risk for germ cell tumors.

Patients with resistant ovary syndrome (Savage syndrome) also have hypergonadotropic hypogonadism, but they have normal ovarian germ cell reserve as evidenced by normal antral follicle counts. Instead, they have FSH receptor gene mutations or post-receptor signaling defects. Since they do not have ovarian failure despite the absence of menses, they are termed pseudo-ovarian failure. Aromatase enzyme deficiencies, 17-hydroxylase gene mutations and LH receptor gene mutations may also present with elevated gonadotropins and normal ovarian germ cell reserve.

Treatment

Once a diagnosis is established, appropriate treatment can be implemented. Treatment of these diverse disorders often requires consultation with other specialists. The treatment of primary and secondary amenorrhea may involve medical management, surgical management, and patient specific counseling.

Medical management should be directed at treating the underlying condition, preventing undesirable complications, and addressing reproductive concerns. Patients with hypothyroidism or hyperprolactinemia are two groups of amenorrheic patients readily treated medically. Thyroid hormone replacement rapidly corrects amenorrhea associated with hypothyroidism. Likewise, prolactinomas are usually slow growing and respond well to dopamine agonists such as bromocriptine or cabergoline. Patients with PCOS have amenorrhea secondary to anovulation. Lack of luteal progesterone and unopposed estrogen places them at risk for endometrial hyperplasia and carcinoma. Therefore, cyclic progestin administration may be necessary to prevent these complications. Alternatively, ovulation induction may be desirable if pregnancy is wanted. In addition, PCOS patients often have insulin resistance and are at risk for diabetes and metabolic syndrome. Beginning an insulin-sensitizing agent to potentially prevent these complications may be considered, but this recommendation is still under active investigation. All hypogonadal patients are by definition estrogen deficient and therefore subject to increased risk of premature osteopenia and osteoporosis. Again, treatment should be considered to prevent this unwarranted complication. Finally, many patients are concerned with reproductive options. For those patients with diagnoses amenable to potential conception, ovulation induction versus contraception should be offered. Other patients with ovarian failure or mullerian anomalies often require referral for assisted reproductive technologies in order to conceive.

For those patients with diagnoses requiring surgical intervention, appropriate referral is imperative. Surgery is necessary to restore anatomy, remove tumors, or to prevent the malignant transformation of Y chromosome containing gonads. Uterine outflow tract abnormalities and Asherman's syndrome should be corrected by an appropriately trained gynecologist or reproductive endocrinologist. Neurosurgical intervention may be required for other tumors of the CNS. Lastly, any patient diagnosed with a Y chromosome by karyotype requires a gonadectomy to prevent the development of germ cell tumors. In patients with AIS, the gonads are allowed to remain in situ until after puberty to facilitate more normal breast formation.

Counseling is an important aspect of treatment of amenorrhea. Patients are often concerned that amenorrhea is a sign of a significant problem. Some patients are given information that may have devastating implications for their future fertility and self-identity and others may learn about some undesirable health effects associated with their diagnosis. Therefore, it is critical to provide supportive counseling and carefully discuss all the ramifications of the diagnosis. Finally, counseling may provide a primarily therapeutic role in treating anorexia and encouraging weight gain and exercise reduction.

Suggested Reading

1. Timmreck LS, Reindollar RH. Contemporary issues in primary amenorrhea. Obstet Gynecol Clin North Am 2003; 30:287-302.

2. Reindollar RH, Novak M, Tho SP et al. Adult-onset amenorrhea: A study of 262 patients. Am J Obstet Gynecol 1986; 155:531-543.

3. Apgar BS. Diagnosis and management of amenorrhea. Clinics in Family Medicine 2002.

4. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility, 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2004.

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