Background
Amenorrhea is the absence of menstrual bleeding.[1] Amenorrhea is a normal feature in prepubertal, pregnant, and postmenopausal females. In females of reproductive age, diagnosing amenorrhea is a matter of first determining whether pregnancy is the etiology. In the absence of pregnancy, the challenge is to determine the exact cause of absent menses.[2]
Primary amenorrhea is the failure of menses to occur by age 16 years, in the presence of normal growth and secondary sexual characteristics. If by age 13 menses has not occurred and the onset of puberty, such as breast development, is absent, a workup for primary amenorrhea should start.
Secondary amenorrhea is defined as the cessation of menses sometime after menarche has occurred. Oligomenorrhea is defined as menses occurring at intervals longer than 35 days.
No consensus has been reached regarding the point at which oligomenorrhea becomes amenorrhea. Some authors suggest the absence of menses for 6 months constitutes amenorrhea, but the basis for this recommendation is unclear. For a postmenarchal girl or a reproductive-aged woman to experience a menstrual cycle interval of more than 90 days is statistically unusual. Practically speaking, this should be an indication for an evaluation to seek the cause.
This article addresses the evaluation and treatment of women with secondary amenorrhea who have no evidence of androgen excess. Women with amenorrhea who do have evidence of androgen excess, such as hirsutism, virilization, or sexual ambiguity, should be evaluated differently from women with amenorrhea alone.
Pathophysiology
The menstrual cycle is an orderly progression of coordinated hormonal events in the female body that stimulates growth of a follicle to release an egg and prepare a site for implantation if fertilization should occur. Menstruation occurs when an egg released by the ovary remains unfertilized; subsequently, the soggy decidua of the endometrium (which was primed to receive a fertilized egg) is sloughed in a flow of menses in preparation for another cycle.
The menstrual cycle can be divided into 3 physiologic phases: follicular, ovulatory, and luteal. Each phase has a distinct hormonal secretory milieu. Consideration of the target organs of these reproductive hormones (hypothalamus, pituitary, ovary, uterus) is helpful for identifying the disease process responsible for a patient’s amenorrhea.
Follicular phase
In physiologic terms, the first day of menses is considered the first day of the menstrual cycle. The following 13 days of the cycle are designated the follicular phase. As levels of progesterone, estradiol, and inhibin decline 2-3 days before menses, the pituitary begins to release higher levels of follicle-stimulating hormone (FSH), which recruits oocytes for the next menstrual cycle. The hypothalamus is the initiator of the follicular phase via gonadotropin-releasing hormone (GnRH).
The GnRH pump in the hypothalamus releases GnRH in a pulsatile fashion into the portal vessel system surrounding the anterior pituitary gland. GnRH interacts with the anterior pituitary gland to stimulate release of FSH in the follicular phase. FSH is secreted into the circulation and communicates with the granulosa cells surrounding the developing oocytes.
As FSH increases during the early portion of the follicular phase, it meshes with granulosa cells to stimulate the aromatization of androgens into estradiol. The increase in estradiol and FSH leads to an increase in FSH-receptor content in the many developing follicles.
Over the next several days, the steady increase of estradiol (E2) levels exerts a progressively greater suppressive influence on pituitary FSH release. Only one selected lead follicle, with the largest reservoir of estrogen, can withstand the declining FSH environment. The remaining oocytes that were initially recruited with the lead follicle undergo atresia. Immediately prior to ovulation, the combination of E2 and FSH leads to the production of luteinizing-hormone (LH) receptors on the granulosa cells surrounding the lead follicle.
During the late follicular phase, estrogen has a positive influence on LH secretion, instead of suppressing pituitary LH secretion as it does early in the follicular phase. To have this positive effect, the E2 level must achieve a sustained elevation for several days. The LH surge promotes maturation of the dominant oocyte, the release of the oocyte and then the luteinization of the granulosa cells and the surrounding theca cells of the dominant follicle resulting in progesterone production.
The appropriate level of progesterone arising from the maturing dominant follicle contributes to the precise timing of the midcycle surge of LH. E2 promotes uterine endometrial gland growth, which allows for future implantation.
Ovulatory phase
Ovulation occurs approximately 34-36 hours after the onset of the LH surge or 10-12 hours after the LH peak and 24-36 hours after peak E2 levels. The rise in progesterone increases the distensibility of the follicular wall and enhances proteolytic enzymatic activity, which eventually breaks down the collagenous follicular wall.
After the ovum is released, the granulosa cells increase in size and take on a yellowish pigmentation characteristic of lutein. The corpus luteum then produces estrogen, progesterone, and androgens and becomes increasingly vascularized.
Luteal phase
The lifespan and steroidogenic capacity of the corpus luteum depends on continued LH secretion from the pituitary gland. The corpus luteum secretes progesterone that interacts with the endometrium of the uterus to prepare it for implantation. This process is termed endometrial decidualization.
In the normal ovulatory menstrual cycle, the corpus luteum declines in function 9-11 days after ovulation. If the corpus luteum is not rescued by human chorionic gonadotropin (hCG) hormone from the developing placenta, menstruation reliably occurs 14 days after ovulation. If conception occurs, placental hCG interacts with the LH receptor to maintain luteal function until placental production of progesterone is well established.
Puberty
At birth, female infants have a predetermined number of primordial follicles that are arrested during meiosis 1 at the diplotene stage of prophase until stimulation at puberty. Until puberty, the hypothalamus is in a quiescent state. At approximately age 8 years, GnRH is synthesized in the hypothalamus and released. The adrenal cortex begins to produce dehydroepiandrostenedione to initiate the start of adrenarche (ie, the development of sexual hair).
The orderly progression of puberty begins with breast budding (thelarche), accelerated growth, and menses (menarche). Pubarche, which is independent from GnRH function, typically occurs between breast budding and accelerated growth but may occur anywhere along the puberty timeline. In the United States, the average age of girls at menarche is 12.6 years, with a range of 9-15 years. (Age 15 years is 2 standard deviations above the mean, while age 16 years is 3 standard deviations above.)
Menarche and sustained menstrual cycles requires normal function of the endocrine axis comprising the hypothalamus, pituitary, and ovaries (see the image below). Any disruption in this axis may result in amenorrhea. Defining the level of primary dysfunction is critical in determining the pathophysiology of amenorrhea.
Hypothalamus, pituitary and ovaries form a functional endocrine axis, known as HPO axis with hormonal regulations and feedback loops. Hypothalamic amenorrhea
Hypothalamic dysfunction results in decreased or inhibited GnRH secretion, which affects the pulsatile release of LH and FSH, causing anovulation. A common cause of amenorrhea is functional hypothalamic amenorrhea.[3] It is characterized by abnormal hypothalamic GnRH secretion, decreased gonadotropin pulsations, low or normal LH concentrations, absent LH surges, abnormal follicular development, and low serum estradiol. Serum FSH concentrations are usually in the normal range, with high FSH-to-LH ratio.[4]
Functional hypothalamic amenorrhea can be caused by eating disorders, exercise, or high levels of prolonged physical or mental stress. This can also include major psychiatric disorders such as depression. Hypothyroidism, hyperthyroidism, sarcoidosis, galactosemia or any severe chronic medical condition may result in amenorrhea.[5]
Congenital GnRH deficiency leads to low gonadotropin levels. When this occurs with anosmia, it is diagnosed as Kallman syndrome. Kallman syndrome may be associated with midline facial defect, renal agenesis, and neurologic deficiency. Most often, it is an X-linked recessive disorder. Autosomal dominant and autosomal recessive inheritances are possible but less common. For detailed information, see Gonadotropin-Releasing Hormone Deficiency in Adults.
Evidence suggests a negative correlation between body fat levels and menstrual abnormalities. A critical body fat level must be present for the reproductive system to function normally.
In some female athletes, the synergistic effects of excessive exercise and disordered eating cause severe suppression of GnRH, leading to low estradiol levels. The female athletic triad, as defined by the American College of Sports Medicine, is characterized by disordered eating, amenorrhea, and osteoporosis.[3] A 2009 study by DeSouza et al found that about half of exercising women could be amenorrheic.[6]
Anorexia nervosa is a serious psychiatric disease with severe medical complications including primary amenorrhea (15%), osteopenia (52%), and osteoporosis (35%).[7]
Functional causes of amenorrhea include severe chronic disease, rapid weight loss, malnutrition, depression or other psychiatric disorders, recreational drug abuse, and psychotropic drug use.
Pituitary amenorrhea
A deficiency in FSH and LH may be a result of GnRH receptor gene mutations. Mutations in the FSH beta gene have been associated with amenorrhea. These women have low FSH and estradiol levels and high LH levels. Primary amenorrhea caused by hyperprolactinemia is a rare condition characterized by the onset of thelarche and pubarche at appropriate ages but arrest of pubertal development before menarche.[8]
Hyperprolactinemia is associated with suppression of the GnRH from the hypothalamus and subsequent inhibition of LH and FSH, suppressed gonadal function and galactorrhea. Prolactinomas are the most common cause of persistent hyperprolactinemia, accounting for 40-50% of pituitary tumors.[9]
Pituitary tumors may suppress gonadotropin secretion, such as in Cushing disease or hypothalamic tumors, craniopharyngioma, or germinoma. Brain injury or cranial irradiation may also result in amenorrhea. Other pituitary causes include empty sella syndrome, pituitary infarct, hemachromatoses, and sarcoidosis.
Ovarian causes of primary amenorrhea
Gonadal dysgenesis most commonly occurs in Turner syndrome (45,X). Accelerated loss of the germ cells in the gonads occurs. The gonads usually contain only fibrous tissue and are called streak gonads. Gonadotropin levels, especially the FSH levels, are high during early childhood and after age 9-10 years.
Additional anomalies associated with Turner syndrome include short stature, webbed neck, coarctation of the aorta (10%), renal abnormalities (50%), hypertension, pigmented nevi, short forth metacarpal and metatarsals, Hashimoto thyroiditis, obesity, and osteoporosis.[3] Depletion of ovarian follicles causes amenorrhea.
Spontaneous 46,XX primary ovarian insufficiency (POI), (also known as premature ovarian failure [POF] and premature menopause) affects 1 in 10,000 women by age 20 years, 1 in 1,000 women by age 30 years, 1 in 250 women by age 35 years, and 1 in 100 women by age 40 years.[10] POI is hypergonadotropic hypogonadism, characterized by oligomenorrhea, estrogen deficiency, and its associated symptoms such as hot flashes, vaginal dryness, dyspareunia, and insomnia. For more detailed information, see Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure.
The fragile X premutation accounts for approximately 6% of cases of overt POI. It is caused by an increased number of CGG repeats in the FMR1 gene located on the long arm of the X chromosome. In the premutation, the number of CGG repeats ranges from 55-200. Approximately 21% of premutation carriers have POF/POI compared with 1% in the general population.[11] Autoimmune oophoritis occurs in 3-4% of POI cases.[12]
Amenorrhea is also seen in pure 46,XX gonadal dysgenesis and in 46,XY gonadal dysgenesis. These women have significantly elevated FSH levels due to the absence of ovarian follicles and reduction in negative feedback on FSH from estradiol and inhibin A and B.
The early stages of testicular formation require the action of several genes, of which one of the earliest and most important is the sex-determining region of the Y chromosome (SRY). In Swyer syndrome, the fetus has a 46,XY karyotype but with mutations of the SRY gene such that the testes never form and antimüllerian hormone is not produced.
As a result, these individuals have a vagina, uterus, and fallopian tubes. Germ cells in the ovaries are lost before birth. The streak gonads must be surgically removed because of the increased risk for developing germ cell tumor. Pure gonadal dysgenesis occurs when the syndrome affects the gonads only and no other dysmorphic features are noted.
Polycystic ovarian syndrome (PCOS) usually presents as secondary amenorrhea, but in some cases may present as primary amenorrhea. See Polycystic Ovarian Syndrome for more information.
Congenital and anatomical abnormalities
A uterus and patent vaginal tract are needed for normal menstrual flow to occur. Female reproductive tract abnormalities account for about one fifth of primary amenorrhea cases. Cyclic pelvic pain is common in girls with disorders of the reproductive tract involving outflow obstruction. Imperforate hymen causes an outflow obstruction. These patients can have blood in the vagina that collects and can result in a perirectal mass. Transverse vaginal septum can be anywhere along the tract between the hymenal ring and cervix.
Vaginal agenesis, or müllerian dysgenesis (also known as Mayer-Rokitansky-Kuster-Hauser [MRKH] syndrome) is caused by agenesis or partial agenesis of the müllerian duct system. It is characterized by congenital aplasia of the uterus and upper two thirds of the vagina in women showing normal development of the secondary sexual characteristics and a normal 46,XX karyotype.[13] The first sign is primary amenorrhea. It affects 1 of 4500 women. It can be associated with renal, vertebral, and, to a lesser extent, auditory and cardiac defects.[13]
Receptor and enzyme defects
Congenital adrenal hyperplasia as a result of 17 alpha-hydroxylase deficiency (CYP17) causes an excess of deoxycortisone to be produced and deficiency of cortisol and adrenal and gonadal sex steroids. Patients with this disorder who experience primary amenorrhea can be either genotypic males (XY) or females (XX).[3]
Vanishing testes syndrome is characterized by genotypic males 46,XY whose gonads do not develop completely. As a result, no testosterone, estrogen, or müllerian-inhibiting substance is produced. These patients appear phenotypically female. The diagnosis is made from the findings of gonadal failure with lack of pubertal progression, high serum FSH and LH concentrations, and male karyotype.
Androgen insensitivity syndrome occurs when patients are resistant to testosterone. It is an X-linked disease. Patients appear as phenotypically normal females. The testes, located internally and sometimes in the labia or inguinal area, do make müllerian-inhibiting hormone, so all müllerian structures, fallopian tubes, uterus, and upper third of the vagina are absent.
Gonadotropin resistance is rare, but inactivating mutations of the receptors for LH and FSH can cause anovulatory amenorrhea.[14]
Aromatase deficiency is also a rare disorder. Aromatase catalyzes the conversion of androgen to estrogen. When estrogen synthesis cannot occur, increased levels of testosterone result and virilization of the female occurs. Often, girls have cystic ovaries and resultant amenorrhea.[15]
Etiology
Amenorrhea can be divided into 2 groups: (1) amenorrhea without evidence of associated androgen excess and (2) amenorrhea with evidence of androgen excess (eg, hirsutism, virilization, sexual ambiguity). For a review of the causes of amenorrhea associated with androgen excess, see Polycystic Ovarian Syndrome.
Causes of primary amenorrhea
Primary amenorrhea usually results from a genetic or anatomic abnormality. Causes of primary amenorrhea (percentages rounded to the nearest tenth) include hypergonadotropic hypogonadism (48.5% of cases), hypogonadotropic hypogonadism (27.8%), and eugonadism (pubertal delay with normal gonadotropins; 23.7%).[16]
The hypergonadotropic hypogonadism category includes patients with abnormal sex chromosomes (ie, Turner syndrome), who make up 29.7% of all primary amenorrhea cases, and those with normal sex chromosomes. The latter group includes both patients who are 46,XX (15.4%) and those who are 46,XY (3.4%).
Hypogonadotropic hypogonadism includes the following:
- Congenital abnormalities
- Endocrine disorders
- Tumor
- Systemic illness (2.6%)
- Eating disorder (2.3%)
Congenital abnormalities that can cause hypogonadotropic hypogonadism include the following:
- Isolated GnRH deficiency (8.3%)
- Forms of hypopituitarism (2.3%)
- Congenital central nervous system (CNS) defects (0.8%)
- Constitutional delay (6%)
Endocrine disorders that can cause hypogonadotropic hypogonadism include the following:
- Congenital adrenal hyperplasia (CAH) (0.8%)
- Cushing syndrome (0.4%)
- Pseudohypoparathyroidism (0.4%)
- Hyperprolactinemia (1.9%)
Tumors that can cause hypogonadotropic hypogonadism include the following:
- Unclassified pituitary adenoma (0.8%)
- Craniopharyngioma (1.1%)
- Unclassified malignant tumor (0.4%)
Eugonadism may result from anatomic abnormalities or intersex disorders. Anatomic abnormalities include congenital absence of the uterus and vagina (CAUV; 16.2%) and cervical atresia (0.4%). Intersex disorders include androgen insensitivity (1.5%), 17-ketoreductase deficiency (0.4%), and inappropriate feedback (5.3%).
Causes of secondary amenorrhea
Disorders associated with a low or normal FSH, which account for 66% of cases of secondary amenorrhea, include the following[17] :
- Weight loss/anorexia
- Nonspecific hypothalamic
- Chronic anovulation including PCOS
- Hypothyroidism
- Cushing syndrome
- Pituitary tumor, empty sella, Sheehan syndrome
Disorders in which the FSH is high (12%) include the following:
- 46XX, spontaneous POI
- Premature ovarian failure due to abnormal karyotype (45,XO)
- Pure gonadal dysgenesis
Disorders associated with a high prolactin level comprise 13% of cases. Anatomic disorders (ie, Asherman syndrome) account for 7%.
Hyperandrogenic states as a cause of secondary amenorrhea (2%) include the following:
- Polycystic ovarian syndrome (PCOS)
- Ovarian tumor
- Nonclassic CAH
- Undiagnosed
Epidemiology
The incidence of primary amenorrhea in the United States is less than 1%.[18] Each year, approximately 5-7% of menstruating women in the US experience 3 months of secondary amenorrhea
No evidence indicates that the prevalence of amenorrhea varies according to national origin or ethnic group. However, local environmental factors related to nutrition and the prevalence of chronic disease undoubtedly have an effect. For instance, the age of the first menses varies by geographic location, as demonstrated by a World Health Organization study comparing 11 countries, which reported a median age of menarche of 13-16 years across centers.
Recent increases in the rates of childhood obesity around the world may also contribute to earlier onset of menarche and increased prevalence of obesity-related menstrual disorders, especially in areas where obesity is more prevalent.[19] Exposure to environmental toxins, namely hormonally active endocrine disruptors, may also result in increased rates of menstrual and reproductive disorders in endemic areas.[20]
Prognosis
Loss of menstrual regularity has been associated with an increased risk of wrist and hip fractures related to reduced bone density, even without the development of amenorrhea. A later menarche and menstrual cycle intervals longer than 32 days have both been associated with increased fracture rates in later years. Young women with ovarian insufficiency that is unresponsive to therapy require hormone replacement to maintain bone density.
Adolescence is a critical period for bone accretion as over half of peak bone mass is achieved during the teenage years.[21] Regular menses is a sign that the ovaries are producing normal amounts of estrogen, androgens, and progesterone, all of which play an important role in building and maintaining bone mass. Late menarche has been associated with a 3-fold increase in the risk of wrist fracture.[22]
In some cases, loss of menstrual regularity is an early sign of declining fertility and impending premature ovarian failure. Also in some cases, follicle depletion progresses to cause irreversible infertility. Approximately 10% of women evaluated for amenorrhea in a tertiary center are found to have premature ovarian failure or primary ovarian insufficiency.
Patient Education
For patients with ovarian insufficiency that persists despite appropriate evaluation and treatment, careful counseling is warranted to stress the need for ongoing attention to the factors that help maintain bone density. Hormone replacement therapy is important for these patients. Other factors to consider are the need for adequate calcium and vitamin D intake (1200-1500 mg/d of elemental calcium and 1000 IU/d of vitamin D) and the need for 20-30 minutes of weight-bearing exercise each day.
For patient education information, see the Women's Health Center, Eating Disorders Center, and Pregnancy and Reproduction Center, as well as Amenorrhea, Anorexia Nervosa, Birth Control Overview, and Birth Control FAQs.
Current evaluation of amenorrhea. Fertil Steril. Sep 2004;82 Suppl 1:S33-9. [Medline].
Pletcher JR, Slap GB. Menstrual disorders. Amenorrhea. Pediatr Clin North Am. Jun 1999;46(3):505-18. [Medline].
Greenspan FSFS1GDG. Basic & clinical endocrinology. 7th ed. McGraw-Hill; 2001.
Santoro N, Filicori M, Crowley WF Jr. Hypogonadotropic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone. Endocr Rev. Feb 1986;7(1):11-23. [Medline].
Current evaluation of amenorrhea. Fertil Steril. Sep 2004;82 Suppl 1:S33-9. [Medline].
De Souza MJ, Toombs RJ, Scheid JL, O'Donnell E, West SL, Williams NI. High prevalence of subtle and severe menstrual disturbances in exercising women: confirmation using daily hormone measures. Hum Reprod. Nov 26 2009;[Medline].
Miller KK, Grinspoon SK, Ciampa J, et al. Medical findings in outpatients with anorexia nervosa. Arch Intern Med. Mar 14 2005;165(5):561-6. [Medline].
Kawano Y, Kamihigashi S, Nakamura S, et al. Delayed puberty associated with hyperprolactinemia caused by pituitary microadenoma. Arch Gynecol Obstet. Sep 2000;264(2):90-2. [Medline].
Crosignani PG. Current treatment issues in female hyperprolactinaemia. Eur J Obstet Gynecol Reprod Biol. Apr 1 2006;125(2):152-64. [Medline].
Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol. Apr 1986;67(4):604-6. [Medline].
Sherman SL. Premature ovarian failure among fragile X premutation carriers: parent-of-origin effect?. Am J Hum Genet. Jul 2000;67(1):11-3. [Medline].
Bakalov VK, Vanderhoof VH, Bondy CA, Nelson LM. Adrenal antibodies detect asymptomatic auto-immune adrenal insufficiency in young women with spontaneous premature ovarian failure. Hum Reprod. Aug 2002;17(8):2096-100. [Medline].
Morcel K, Camborieux L, , Guerrier D. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Orphanet J Rare Dis. 2007;2:13. [Medline].
Huhtaniemi I, Alevizaki M. Gonadotrophin resistance. Best Pract Res Clin Endocrinol Metab. Dec 2006;20(4):561-76. [Medline].
Jones ME, Boon WC, McInnes K, Maffei L, Carani C, Simpson ER. Recognizing rare disorders: aromatase deficiency. Nat Clin Pract Endocrinol Metab. May 2007;3(5):414-21. [Medline].
Reindollar RH, Tho SPT, McDonough PG. Delayed Puberty: an updated study of 326 patients. Transactions of the Gynecological and Obstetrical Society. 1989;8:146-62.
Current evaluation of amenorrhea. Fertil Steril. Nov 2006;86(5 Suppl 1):S148-55. [Medline].
Professional Guide to Diseases (Professional Guide Series). 8th ed. Lippincott Williams & Wilkins; 2005.
Pandey S, Bhattacharya S. Impact of obesity on gynecology. Womens Health (Lond Engl). Jan 2010;6(1):107-17. [Medline].
Phillips KP, Foster WG. Key developments in endocrine disrupter research and human health. J Toxicol Environ Health B Crit Rev. Mar 2008;11(3-4):322-44. [Medline].
Adams Hillard PJ, Nelson LM. Adolescent girls, the menstrual cycle, and bone health. J Pediatr Endocrinol Metab. May 2003;16 Suppl 3:673-81. [Medline].
Diaz A, Laufer MR, Breech LL. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Pediatrics. Nov 2006;118(5):2245-50. [Medline].
Cartwright MM. Eating disorder emergencies: understanding the medical complexities of the hospitalized eating disordered patient. Crit Care Nurs Clin North Am. Dec 2004;16(4):515-30. [Medline].
Eldar-Geva T, Hirsch HJ, Benarroch F, Rubinstein O, Gross-Tsur V. Hypogonadism in females with Prader-Willi syndrome from infancy to adulthood: variable combinations of a primary gonadal defect and hypothalamic dysfunction. Eur J Endocrinol. Feb 2010;162(2):377-84. [Medline].
Blüher S, Shah S, Mantzoros CS. Leptin deficiency: clinical implications and opportunities for therapeutic interventions. J Investig Med. Oct 2009;57(7):784-8. [Medline].
Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. Sep 2 2004;351(10):987-97. [Medline].
Jayasena CN, Nijher GM, Chaudhri OB, Murphy KG, Ranger A, Lim A, et al. Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. J Clin Endocrinol Metab. Nov 2009;94(11):4315-23. [Medline].
Erb TM, Gerschultz K, Gold MA, Sanfilippo JS. Primary amenorrhea in a young adult with sickle cell disease: a case report and brief literature review on adolescent reproductive health and sickle cell disease. J Pediatr Adolesc Gynecol. Dec 2008;21(6):361-70. [Medline].
Karabulut A, Balci Y, Demirlenk S, Semiz S. Gonadal dysfunction and pelvic sonographic findings in females with thalassaemia major. Gynecol Endocrinol. Apr 2010;26(4):307-10. [Medline].
Livshits A, Seidman DS. Fertility issues in women with diabetes. Womens Health (Lond Engl). Nov 2009;5(6):701-7. [Medline].
Bauer J, Cooper-Mahkorn D. Reproductive dysfunction in women with epilepsy: menstrual cycle abnormalities, fertility, and polycystic ovary syndrome. Int Rev Neurobiol. 2008;83:135-55. [Medline].
Weisinger JR, Gonzalez L, Alvarez H, Hernandez E, Carlini RG, Capriles F, et al. Role of persistent amenorrhea in bone mineral metabolism of young hemodialyzed women. Kidney Int. Jul 2000;58(1):331-5. [Medline].
Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. Jan 2004;19(1):41-7. [Medline].
Wang JG, Lobo RA. The complex relationship between hypothalamic amenorrhea and polycystic ovary syndrome. J Clin Endocrinol Metab. Apr 2008;93(4):1394-7. [Medline].
Welt CK. Primary ovarian insufficiency: a more accurate term for premature ovarian failure. Clin Endocrinol (Oxf). Apr 2008;68(4):499-509. [Medline].
Chitrit Y, Zafy S, Pelage JP, Ledref O, Khoury R, Caubel P. Amenorrhea due to partial uterine necrosis after uterine artery embolization for control of refractory postpartum hemorrhage. Eur J Obstet Gynecol Reprod Biol. Jul 2006;127(1):140-2. [Medline].
Iglesias EA, Coupey SM. Menstrual cycle abnormalities: diagnosis and management. Adolesc Med. Jun 1999;10(2):255-73. [Medline].
Aloi JA. Evaluation of amenorrhea. Compr Ther. Oct 1995;21(10):575-8. [Medline].
Speroff L, Glass RH, Kase NG. Amenorrhea. In: Speroff L, Glass RH, Kase NG, eds. Clinical Gynecologic Endocrinology and Infertility. 6th ed. Baltimore, Md: Williams & Wilkins; 1999:422-85.
Garner DM, Olmsted MP, Polivy J. Development and validation of a multidimensional eating disorder inventory for anorexia nervosa and bulimia. Int J Eating Disorders. 1983;2:15-34.
Thelen MH, Farmer J, Wonderlich S, Smith M. A revision of the bulimia test: the BULIT-R. Psychol Assess. 1991;3:119-24.
Marozzi A, Vegetti W, Manfredini E, Tibiletti MG, Testa G, Crosignani PG, et al. Association between idiopathic premature ovarian failure and fragile X premutation. Hum Reprod. Jan 2000;15(1):197-202. [Medline].
Sharma ST, Nestler JE. Prevention of diabetes and cardiovascular disease in women with PCOS: treatment with insulin sensitizers. Best Pract Res Clin Endocrinol Metab. Jun 2006;20(2):245-60. [Medline].
Nestler JE, Stovall D, Akhter N, Iuorno MJ, Jakubowicz DJ. Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril. Feb 2002;77(2):209-15. [Medline].
Teede HJ, Meyer C, Norman RJ. Insulin-sensitisers in the treatment of polycystic ovary syndrome. Expert Opin Pharmacother. Nov 2005;6(14):2419-27. [Medline].
Norman RJ, Homan G, Moran L, Noakes M. Lifestyle choices, diet, and insulin sensitizers in polycystic ovary syndrome. Endocrine. Aug 2006;30(1):35-43. [Medline].
Kreipe RE, Yussman SM. The role of the primary care practitioner in the treatment of eating disorders. Adolesc Med. Feb 2003;14(1):133-47. [Medline].
Golden NH, Jacobson MS, Schebendach J, Solanto MV, Hertz SM, Shenker IR. Resumption of menses in anorexia nervosa. Arch Pediatr Adolesc Med. Jan 1997;151(1):16-21. [Medline].
Jacoangeli F, Masala S, Staar Mezzasalma F, Fiori R, Martinetti A, Ficoneri C, et al. Amenorrhea after weight recover in anorexia nervosa: role of body composition and endocrine abnormalities. Eat Weight Disord. Mar 2006;11(1):e20-6. [Medline].
Brambilla F, Monteleone P, Bortolotti F, Dalle Grave R, Todisco P, Favaro A, et al. Persistent amenorrhoea in weight-recovered anorexics: psychological and biological aspects. Psychiatry Res. Jun 15 2003;118(3):249-57. [Medline].
Grinspoon S, Miller K, Coyle C, Krempin J, Armstrong C, Pitts S, et al. Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin Endocrinol Metab. Jun 1999;84(6):2049-55. [Medline].
Miller KK, Lee EE, Lawson EA, Misra M, Minihan J, Grinspoon SK, et al. Determinants of skeletal loss and recovery in anorexia nervosa. J Clin Endocrinol Metab. Aug 2006;91(8):2931-7. [Medline].
Hartard M, Kleinmond C, Kirchbichler A, Jeschke D, Wiseman M, Weissenbacher ER, et al. Age at first oral contraceptive use as a major determinant of vertebral bone mass in female endurance athletes. Bone. Oct 2004;35(4):836-41. [Medline].
Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, Hirschberg AL. Oral contraceptives improve endothelial function in amenorrheic athletes. J Clin Endocrinol Metab. Jun 2005;90(6):3162-7. [Medline].
Gidwani GP. Amenorrhea in the athlete. Adolesc Med. Jun 1999;10(2):275-90, vii. [Medline].
Warren MP, Fried JL. Hypothalamic amenorrhea. The effects of environmental stresses on the reproductive system: a central effect of the central nervous system. Endocrinol Metab Clin North Am. Sep 2001;30(3):611-29. [Medline].
Falsetti L, Gambera A, Barbetti L, Specchia C. Long-term follow-up of functional hypothalamic amenorrhea and prognostic factors. J Clin Endocrinol Metab. Feb 2002;87(2):500-5. [Medline].
Manuel M, Katayama PK, Jones HW Jr. The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am J Obstet Gynecol. Feb 1 1976;124(3):293-300. [Medline].
Bondy CA. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. Jan 2007;92(1):10-25. [Medline].
Adhikary AK, Banik U, Numaga J, Suzuki E, Inada T, Okabe N. Heterogeneity of the fibre sequence in subgenus C adenoviruses. J Clin Pathol. Jun 2004;57(6):612-7. [Medline]. [Full Text].
Laml T, Preyer O, Umek W, Hengstschlager M, Hanzal H. Genetic disorders in premature ovarian failure. Hum Reprod Update. Sep-Oct 2002;8(5):483-91. [Medline].
Bakalov VK, Anasti JN, Calis KA, Vanderhoof VH, Premkumar A, Chen S, et al. Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure. Fertil Steril. Oct 2005;84(4):958-65. [Medline].
Davis SR. Premature ovarian failure. Maturitas. Feb 1996;23(1):1-8. [Medline].
DiPiro JT TRYG. Hormone therapy in women. Pharmacotherapy. In: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005:1493-513.
Davis SR. The therapeutic use of androgens in women. J Steroid Biochem Mol Biol. Apr-Jun 1999;69(1-6):177-84. [Medline].
Arnhold IJ, Lofrano-Porto A, Latronico AC. Inactivating mutations of luteinizing hormone beta-subunit or luteinizing hormone receptor cause oligo-amenorrhea and infertility in women. Horm Res. 2009;71(2):75-82. [Medline].
Capito C, Leclair MD, Arnaud A, David A, Baron S, Corradini N, et al. 46,XY pure gonadal dysgenesis: clinical presentations and management of the tumor risk. J Pediatr Urol. Feb 2011;7(1):72-5. [Medline].
Fedele L, Bianchi S, Frontino G, Ciappina N, Fontana E, Borruto F. Laparoscopic findings and pelvic anatomy in Mayer-Rokitansky-Küster-Hauser syndrome. Obstet Gynecol. May 2007;109(5):1111-5. [Medline].
[Guideline] Identifying and treating eating disorders. Pediatrics. Jan 2003;111(1):204-11. [Medline].
Quintos JB, Krotz S, Vogiatzi MG, Kralickova M, New MI. Partial hypogonadotropic hypogonadism associated with the Leu266Arg and Gln106Arg mutation of the gonadotropin-releasing hormone receptor. J Pediatr Endocrinol Metab. Feb 2009;22(2):181-5. [Medline].
The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. Feb 7 1996;275(5):370-5. [Medline].
Print
