amenorrhea wang ling obstetrics & gynecology hospital of fudan university

AMENORRHEAAMENORRHEA

Wang LingWang Ling

Obstetrics & Gynecology Hospital of Fudan UniversityObstetrics & Gynecology Hospital of Fudan University

menstrual cycle physiologymenstrual cycle physiology

hypothalamus secrete GnRH in a pulsatile fashion

GnRH stimulates pituitary secrete FSH and LHwhich promotes ovarian follicular development and ovulation

ovarian follicle secretes E2after ovulation, the follicle is converted to corpus luteumand P is secreted in addition to E2

A complex hormonal interaction for normal menstruation


menstrual cycle physiologymenstrual cycle physiology

●If pregnancy not occur, E2 and P secretion decrease and withdrawal bleeding begins

●If any of the components (hypothalamus, pituitary, ovary, uterus, and outflow tract) are nonfunctional, bleeding cannot occur


ContentsContents

definition and Classification of amenorrhea

etiology of amenorrhea

Diagnosis of amenorrhea

The management of amenorrhea44

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Definition of AmenorrheaDefinition of Amenorrhea

• Primary amenorrheaPrimary amenorrhea Girls experienced menarche at increasingly younger ages during the past

century

the absence of menses at age 13 years when there is no visible development of

secondary sexual characteristics

or age 15 years in the presence of normal secondary sexual characteristics

• Secondary amenorrheaSecondary amenorrhea absence of menstruation for three normal menstrual cycles or 6 months


CategoriesCategories

• hypothalamic amenorrhea

• pituitary amenorrhea

• ovarian amenorrhea

• uterine amenorrhea

• anatomic abnormalities of the reproductive tract


classes of amenorrhea (WHO)classes of amenorrhea (WHO)

• Group I : Group I : no evidence of endogenous estrogen production

normal or low FSH

normal prolactin

no lesion in the hypothalamic-pituitary region

• Group II : Group II : evidence of estrogen production

normal prolactin and FSH

• Group III : Group III : elevated FSH indicating gonadal insufficiency or failure


Etiology of AmenorrheaEtiology of Amenorrhea

• whether secondary sexual characteristics are present

• absence of secondary sexual characteristics indicates: never exposed to estrogen


Amenorrhea without Secondary Sexual Characteristics

• breast development is the first sign of estrogen exposure in puberty, patients without secondary sexual characteristics typically have primary, not secondary, amenorrhea

• categorize the causes of amenorrhea in the absence of breast development on the basis of gonadotropin status


Hypergonadotropic Hypogonadism Associated with Hypergonadotropic Hypogonadism Associated with Absence of Secondary Sexual CharacteristicsAbsence of Secondary Sexual Characteristics

• Gonadal dysgenesis: abnormal development of the gonads

• is associated with high levels of LH and FSH because the gonad fails to produce the steroids and inhibin that would feed back to pituitary gland to suppress LH and FSH

• Karyotypic abnormalities are common with primary amenorrhea

• approximately 30% primary amenorrhea had an associated karyotypic abnormality


Turner syndromeTurner syndrome

• Turner syndrome (45,X) represent the most common form of hypergonadotropic hypogonadism with primary amenorrhea.


In addition to gonadal failureshort staturewebbed neckshield chestcubitus valguslow hair linehigh arched palatemultiple pigmented nevishort fourth metacarpals

Other disorders associated with primary Other disorders associated with primary amenorrhea include:amenorrhea include:

abnormal X chromosomes

mosaicism

pure gonadal dysgenesis (46,XX and 46,XY with gonadal streaks)

Rare enzyme deficiencies that prevent normal estrogen production

Rare gonadotropin receptor inactivating mutations

Individuals with these conditions have gonadal failure and cannot synthesize ovarian steroids.

Most patients with these conditions have primary amenorrhea and lack secondary sexual characteristics


Other Causes of Primary Ovarian Failure without Other Causes of Primary Ovarian Failure without Secondary Sexual CharacteristicsSecondary Sexual Characteristics

• Severe damage to the ovaries before the onset of puberty• Ovarian dysfunction can occur in association with irradiation

of the ovaries, chemotherapy, or combinations of radiation and other chemotherapeutic agents

• Other causes of premature ovarian failure (also known as primary ovarian insufficiency) are more commonly associated with amenorrhea after the development of secondary sexual characteristics


Hypogonadotropic Hypogonadism Associated with the Hypogonadotropic Hypogonadism Associated with the Absence of Secondary Sex CharacteristicsAbsence of Secondary Sex Characteristics

• hypothalamus fails to secrete adequate GnRH or pituitary disorder associated with inadequate production or release of pituitary gonadotropins

• Physiologic Delay

• Kallmann Syndrome

• Other Causes of Gonadotropin-Releasing Hormone Deficiency


Amenorrhea Associated with a Lack of Secondary Amenorrhea Associated with a Lack of Secondary Sexual CharacteristicsSexual Characteristics

• Abnormal pelvic examination 5α-reductase deficiency, 17, 20-lyase deficiency, or 17α-hydroxylase deficiency in XY individual Congenital lipoid adrenal hyperplasia Luteinizing hormone receptor defect

• Hypergonadotropic hypogonadism Gonadal dysgenesis Follicle-stimulating hormone receptor defect Partial deletion of X chromosome Sex chromosome mosaicism Environmental and therapeutic ovarian toxins 17α-hydroxylase deficiency in XX individual Galactosemia Congenital lipoid adrenal hyperplasia in XX individualHypogonadotropic hypogonadism Physiologic delay Kallmann syndrome Central nervous system tumors Hypothalamic/pituitary dysfunction


Evaluation of Amenorrhea Associated with the Absence Evaluation of Amenorrhea Associated with the Absence of Secondary Sexual Characteristicsof Secondary Sexual Characteristics

• careful history and physical examination

• serum FSH and LH levels to differentiate hypergonadotropic and hypogonadotropic of hypogonadism

• Turner syndrome: coarctation of the aorta (up to 30%) and thyroid dysfunction, echocardiography and thyroid function studies

• karyotype abnormal and contains the Y chromosome, as in gonadal dysgenesis, the gonads should removed to prevent tumors

• karyotype is normal, FSH is elevated, consider 17α-hydroxylase deficiency because it may be a life-threatening disease

• FSH level low, diagnosis of hypogonadotropic hypogonadism. Central nervous system lesions should be ruled out by imaging using CT or MRI, especially if galactorrhea, headaches, or visual field defects

• Physiologic delay is a diagnosis of exclusion that is difficult to distinguish from insufficient GnRH secretion


Treatment of Amenorrhea Associated with the Absence Treatment of Amenorrhea Associated with the Absence of Secondary Sexual Characteristicsof Secondary Sexual Characteristics

• Individuals with primary amenorrhea associated with gonadal failure and hypergonadotropic hypogonadism need cyclic estrogen and progestogen therapy to initiate, mature, and maintain secondary sexual characteristics

• Prevention of osteoporosis is an additional benefit of estrogen therapy

• If possible, therapeutic measures are aimed at correcting the primary cause of amenorrhea


Amenorrhea with Secondary Sexual Characteristics Amenorrhea with Secondary Sexual Characteristics and Abnormalities of Pelvic Anatomyand Abnormalities of Pelvic Anatomy

1. Müllerian anomalies

2. Androgen insensitivity

3. True hermaphrodism

4. Absent endometrium

5. Asherman syndrome


Amenorrhea with Secondary Sexual Characteristics Amenorrhea with Secondary Sexual Characteristics and Abnormalities of Pelvic Anatomyand Abnormalities of Pelvic Anatomy

• Outflow and Müllerian Anomalies

1. blockage of the outflow tract,

outflow tract is missing

or no functioning uterus.

2. for menses occur, endometrium must be functional and must be patency of the cervix and vagina

3. Most müllerian abnormalities have normal ovarian function, thus will have normal secondary sexual characteristic development


Absence of Functioning Endometrium

• Amenorrhea may occur if there is no functioning endometrium

• Asherman syndrome

• more common with secondary amenorrhea or hypomenorrhea

• occur in patients with risk factors for endometrial or cervical scarring


Androgen InsensitivityAndrogen Insensitivity

• Phenotypic females with complete congenital androgen insensitivity develop secondary sexual characteristics but do not have menses

• Genotypically, male (XY) but have a defect prevents normal androgen receptor function, leading to the development of the female phenotype

• Serum testosterone in normal male range

• vagina may be absent or short


Evaluation Amenorrhea, Normal Secondary Sexual Characteristics, Evaluation Amenorrhea, Normal Secondary Sexual Characteristics, Suspected Anatomic AbnormalitiesSuspected Anatomic Abnormalities

• Most congenital abnormalities can be diagnosed by physical examination:

• An imperforate hymen is diagnosed by the presence of a bulging membrane that distends during Valsalva maneuver, Ultrasonography or MRI

• differentiate a transverse septum or complete absence of the cervix and uterus from a blind vaginal pouch in a male pseudohermaphrodite. Androgen insensitivity is likely when pubic and axillary hair is absent

• An absent endometrium is an outflow tract abnormality that cannot be diagnosed by physical examination with primary amenorrhea

• Asherman syndrome cannot be diagnosed by physical examination. It is diagnosed by performing hysterosalpingography, saline infusion sonography (also known as saline hysterogram), or hysteroscopy


Treatment with Amenorrhea, Normal Secondary Sexual Characteristics, and Abnormalities of Pelvic Anatomy

• imperforate hymen, making a cruciate incision to open the vaginal orifice

• transverse septum, surgical removal is required

• Hypoplasia or absence of the cervix in the presence of a functioning uterus is more difficult to treat than other outflow obstructions

• vagina is absent or short, progressive dilation to making it functional

• complete androgen insensitivity, the testes be removed after pubertal development is complete to prevent malignant degeneration

• Adhesions in the cervix and uterus (Asherman syndrome) be removed using hysteroscopic resection with scissors or electrocautery


Amenorrhea with Secondary Sexual Characteristics Amenorrhea with Secondary Sexual Characteristics and Normal Pelvic Anatomyand Normal Pelvic Anatomy

• the most common causes are pregnancy

• polycystic ovarian syndrome

• Hyperprolactinemia

• primary ovarian insufficiency (also known as premature ovarian failure)

• hypothalamic dysfunction

• Pregnancy must be considered in all women of reproductive age with amenorrhea


Polycystic Ovarian SyndromePolycystic Ovarian Syndrome

• associated with hyperandrogenism, ovulatory dysfunction, and polycystic ovaries

• exclude patients with significantly elevated prolactin, significant thyroid dysfunction, adult-onset congenital adrenal hyperplasia, and androgen-secreting neoplasms from being classified as PCOS

• Rotterdam 2003 criteria required two of three of the following for PCOS diagnosis: hyperandrogenism, oligomenorrhea or amenorrhea, polycystic ovaries by ultrasound

• Even though PCOS usually causes irregular bleeding rather than amenorrhea, it remains one of the most common causes of amenorrhea

• In patients who are hirsute and amenorrheic and appear to have PCOS, androgen-secreting adrenal tumors and congenital adrenal hyperplasia should be considered


HyperprolactinemiaHyperprolactinemia

• is a common cause of anovulation in women

• Elevation of prolactin produces abnormal GnRH secretion, which can lead to menstrual disturbances

• other central nervous system (CNS) lesions that disrupt the normal transport of dopamine down the pituitary stalk, and by medications that interfere with normal dopamine

• If elevated TSH and elevated prolactin levels are found together, the hypothyroidism should be treated before hyperprolactinemia is treated


Primary Ovarian Insufficiency (Premature Ovarian Primary Ovarian Insufficiency (Premature Ovarian Failure)Failure)

• presence of amenorrhea for 4 months or more, two serum FSH levels in the menopausal range for who is less than 40 years of age

• decreased follicular endowment or accelerated follicular atresia

• If the ovary does not develop or stops its hormone production before puberty, the patient will not develop secondary sexual characteristics without exogenous hormone therapy. If ovarian insufficiency begins later in life, the woman will have normal secondary sexual characteristics

• a heterogenous disorder with many potential causes


Pituitary and Hypothalamic LesionsPituitary and Hypothalamic Lesions

• Tumors of the hypothalamus or pituitary, prevent appropriate hormonal secretion

• Pituitary Lesions; Sheehan syndrome, postpartum necrosis of pituitary resulting from a hypotensive episode

• If hypopituitarism occurs before puberty, menses and secondary sexual characteristics will not develop


Altered Hypothalamic Gonadotropin-Releasing Altered Hypothalamic Gonadotropin-Releasing Hormone SecretionHormone Secretion

• Abnormal secretion of GnRH accounts for one-third of amenorrhea

• When decrease in GnRH pulsatility is severe, amenorrhea results

• Decreased leptin levels are associated with hypothalamic amenorrhea, regardless of whether it is caused by exercise, eating disorders, or idiopathic factors


Eating DisordersEating Disorders

• Anorexia nervosa is an eating disorder that affects 5% to 10% of adolescent women

• refusal to maintain body weight above 15% below normal, an intense fear of becoming fat, altered perception of one's body image and amenorrhea


Weight Loss and Dieting, etcWeight Loss and Dieting, etc

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

Exercise

decrease in the frequency of GnRH pulses

Stress

Obesity

Other Hormonal Factors


Evaluation with Amenorrhea in the Presence of Normal Pelvic Anatomy and Normal Secondary

Sexual Characteristics


• pregnancy test (hCG) in a reproductive-age

Clinical assessment of estrogen status

Serum TSH

Serum prolactin

Serum FSH level

Vaginal ultrasound for assessment of antral follicle count in the ovaries can

be considered

Imaging of the pituitary and hypothalamic assessment if prolactin is

elevated or if hypothalamic amenorrhea is suspected

Treatment for Amenorrhea in the Presence of Normal Pelvic Anatomy and Normal Secondary Sexual Characteristics


pregnant may be counseled regarding the options for continued care

thyroid abnormalities are detected, thyroid hormone, radioactive iodine, or antithyroid drugs administered as appropriate

hyperprolactinemia, treatment may include discontinuation of contributing medications, treatment with dopamine agonists such as bromocriptine or cabergoline, and, rarely, surgery for particularly large pituitary tumors

POI, hormone replacement to diminish symptoms and to prevent osteoporosis

Gonadectomy is required when a Y cell line is present

Study QuestionsStudy Questions


A 15-year-old girl, she has never had a period. She seemed to grow and develop breasts at the same time as the other girls in school, but that she has not yet started to menstruate. She is active in sports at her school and plays the piano. an examination reveals Tanner IV breast and pelvic examination reveals a blind vaginal pouch. Ultrasound confirms absence of a uterus. An FSH level is normal at 5.8 mIU/mL. The next step in the evaluation is:

A MRI of the pituitary

B Karyotype

C Visual field testing

D Trial of estrogen/progesterone to stimulate bleeding

E Creation of a neovagina using graduated dilators


A 24-year-old female with the complaint of missed menstrual cycles. She states her period has never been regular, and that in the past it was common for her to skip a month or two between cycles. Now, however, she has not had a period in the past 7 months. She denies sexual activity, reports no medical problems, and her only prescribed medication is a face wash for acne. On review of systems she reports a weight gain of 7kg over the past year. Her laboratory test reveals an FSH level of 8.7 mIU/mL, LH of 22.2 mIU/mL, estradiol of 45 pg/mL, TSH of 2.2 mIU/mL, prolactin of 12 ng/mL, and total testosterone of 98 ng/dL. The most likely diagnosis is:

A Premature ovarian insufficiency

B Polycystic ovary syndrome

C Prolactinoma

D Functional hypothalamic amenorrhea

E Hypothyroidism


A 27-year-old woman complaining of not getting her period. She came off of the birth control pill 9 months ago to attempt pregnancy and has not had a period since. Multiple home pregnancy tests have been negative. She states she underwent menarche at the age of 12 years, and that she did not always get a period every month during high school but was told this was normal because she was an athlete. She continues to be very athletic, running 5 to 6 times per week and also bikes. She has no hirsutism or acne. The most likely reason for her amenorrhea is:

A Polycystic ovary syndrome B Müllerian agenesis C Functional hypothalamic amenorrhea D Prolactinoma E Swyer syndrome


A 32-year-old woman returns to your care 5 months after the birth of her child. She had a postpartum hemorrhage following vaginal delivery of her son, requiring emergency surgery and multiple blood transfusions. She complains of fatigue, constipation, and states that her periods have not returned despite the fact that she has not been able to breastfeed. Her laboratory test reveals an FSH level of 1.2 mIU/mL, TSH of 0.3 IU/mL, and prolactin of 1 ng/mL. The most likely etiology of her secondary amenorrhea is:

A Asherman’s syndrome B Polycystic ovary syndrome C Functional hypothalamic amenorrhea D Sheehan’s syndrome E Kallman’s syndrome


A 26-year-old female is referred to your office by her primary care doctor. She reports regular menses in the past, but has not had a period for 2 years. She did not bleed after a course of progesterone prescribed by her doctor. On examination she is 58 inches tall, has normal secondary sexual characteristics. Laboratory test reveals an FSH level of 82 mIU/mL and estradiol of 26 pg/mL. What is the next step in her evaluation?

A Pelvic ultrasound B Total testosterone C Karyotype D Pituitary MRI E Trial of oral contraceptive pills


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amenorrhea wang ling obstetrics & gynecology hospital of fudan university

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