AmenorrheaUNC School of Medicine

Obstetrics and Gynecology ClerkshipCase Based Seminar Series

Objectives for Amenorrhea

Define amenorrhea and oligomenorrhea

Explain the pathophysiology and identify the etiologies of amenorrhea and oligomenorrhea

Describe the symptoms and physical examination findings of amenorrhea and oligomenorrhea

Discuss the steps in the evaluation and management of amenorrhea and oligomenorrhea

Describe the consequences of untreated amenorrhea and oligomenorrhea

Amenorrhea – absence of menses Primary amenorrhea – absence of menarche

Absence of menarche by age 14 without secondary sexual characteristics Absence of menarche by age 16 with secondary sexual characteristics

Secondary amenorrhea – absence of menses in a previously menstruating woman

Absence of menses for > 6 months or duration of 3 menstrual cycles

Oligomenorrhea – reduction in frequency of menses Cycle lengths > 35 days, but < 6 months

Definition

Pregnancy Thyroid disease Hyperprolactinemia

Prolactinoma Hypergonadotropic hypogonadism

Gonadal dysgenesis (i.e. Turner syndrome) Premature ovarian failure

Hypogonadotropic hypogonadism Constitutional delay of puberty Congenital GnRH deficiency (Kallman syndrome) Functional hypothalamic amenorrhea (i.e. Anorexia or Bulimia nervosa) CNS tumor (i.e. Craniopharyngioma)

Normogonadotropic Congenital (i.e. Mullerian agenesis, Androgen Insensitivity syndrome) Outflow tract obstruction (i.e. Imperforate hymen, Transverse vaginal septum) Hyperandrogenic anovulation (i.e. PCOS, Cushing’s disease)

Primary Amenorrhea: Etiology

Most common etiologies: Chromosomal abnormalities causing gonadal dysgenesis – 50% Hypothalamic hypogonadism – 20% Absence of the uterus, cervix, or vagina – 15% Transverse vaginal septum or imperforate hymen – 5% Pituitary disease – 5%

Primary Amenorrhea: Etiology

Primary Amenorrhea: History

Findings Association

Completion of stages of puberty? Development of axillary and pubic hair? Breast development?

Ovarian or pituitary failureChromosomal abnormality

Family history of delayed or absent puberty? Familial disorderConstitutional delay of puberty

Height relative to family members? Turner’s syndrome

Symptoms of virilization? PCOSOvarian or adrenal tumorPresence of Y chromosome

Recent stress? Change in weight, diet, or exercise? Functional hypothalamic amenorrhea

Medications (i.e. antidepressants, antipsychotics)? Hyperprolactinemia

Galactorrhea? Hyperprolactinemia

Headaches, visual field defects, fatigue, polyuria or polydipsia?

Hypothalamic-pituitary disease

Evaluation of pubertal development (height, weight) and growth chart Breast development (Tanner staging) Evaluation for features of Turner’s syndrome

Webbed neck, low hair line, shield chest, widely spaced nipples Examine skin for hirsutism, acne, striae, increased pigmentation, and

vitiligo

Pelvic exam Clitoral size Intactness of hymen Depth of vagina Presence of vaginal septum Presence of cervix, uterus, and ovaries

Primary Amenorrhea: Physical Exam

Tanner Stages

Stage 1: Prepubertal, no palpable breast tissue or pubic hair.

Stage 2: Development of breast bud; sparse, straight pubic hair.

Stage 3: Enlargement of breast; pubic hair darker, coarser, and curlier.

Stage 4: Areola and papilla project above the breast; pubic hair adult-like in appearance.

Stage 5: Recession of areola to match contour of breast; pubic hair extends to thigh.

Figure from: Roede, MJ, van Wieringen, JC. Growth diagrams 1980: Netherlands third nation-wide survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with permission from the author.

Primary Amenorrhea: Evaluation

Secondary sexual characteristics present?

Measure FSH Perform ultrasound of uterus

Karyotype analysis

FSH > 20 Uterus absent or abnormal

Uterus present or normal

Turner’s syndrome

Hypergonadotropichypogonadism

Hypogonadotropichypogonadism

46,XX

FSH < 5

46,XY

Premature ovarian failure

Karyotype analysis

46,XX 45,XO

Müllerian agenesis

Androgen insensitivity syndrome

Outflow obstruction

Imperforate hymenTransverse vaginal

septum

Evaluate for 2° amenorrhea

No Yes

No Yes

Hypothalamic amenorrhea Constitutional delay

of puberty Kallman syndrome CNS tumor

PCOS Cushing’s

Pregnancy Thyroid disease Hyperprolactinemia

Prolactinoma Breastfeeding, Breast stimulation Medication (i.e. Antipsychotics, Antidepressants)

Hypergonadotropic hypogonadism Postmenopausal ovarian failure Premature ovarian failure

Hypogonadotropic hypogonadism Functional hypothalamic amenorrhea (i.e. Anorexia or Bulimia nervosa) CNS tumor (i.e. Craniopharyngioma) Sheehan’s syndrome Chronic illness

Normogonadotropic Outflow tract obstruction (i.e. Asherman’s syndrome, Cervical stenosis) Hyperandrogenic anovulation (i.e. PCOS, Cushing’s disease, CAH)

Secondary Amenorrhea/Oligomenorrhea: Etiology

Most common etiologies: Ovarian disease – 40% Hypothalamic dysfunction – 35% Pituitary disease – 19% Uterine disease – 5% Other – 1%

Secondary Amenorrhea/Oligomenorrhea: Etiology

Secondary Amenorrhea/Oligomenorrhea: History

Findings Association

Recent stress? Change in weight, diet, or exercise? Functional hypothalamic amenorrhea

Development of acne, hirsutism, striae, central obesity, increased skin pigmentation or deepening voice?

PCOSCushing’s diseaseOvarian or adrenal tumor

Medications (i.e. antidepressants, antipsychotics)? Hyperprolactinemia

Chronic illness? Functional hypothalamic amenorrhea

Headaches, visual field defects, fatigue, polyuria or polydipsia?

Hypothalamic-pituitary disease

Symptoms of estrogen deficiency (hot flashes, vaginal dryness, decreased libido, or poor sleep)?

Premature ovarian failurePostmenopausal ovarian failure

Galactorrhea? Hyperprolactinemia

History of obstetrical catastrophe, severe bleeding, D&C, endometritis, or other infection?

Sheehan’s syndromeAsherman’s syndrome

General Evaluation of height, weight, and BMI Examine skin for hirsutism, acne, striae, acanthosis nigricans, thickness or

thinness, and easy bruisability

Thyroid exam Breast exam

Express for galactorrhea

Pelvic exam Atrophy Vaginal dryness

Secondary Amenorrhea/Oligomenorrhea: Physical

Exam

Secondary Amenorrhea/Oligomenorrhea:

EvaluationNegative urine pregnancy test

Progestin challenge test

Negative MRIConsider other

causes

No withdrawal bleed

Prolactin < 100 ng/mL Prolactin > 100 ng/mL

Check FSH

Estrogen/progestinChallenge test

Normogonadotropichypogonadism

Hypergonadotrpoic hypogonadism

Withdrawal bleed

FSH > 20 IU/LOutflow obstruction

• Medication

MRI to evaluate for pituitary tumor

Normal MRIHypogonadotropic

hypogonadism

MRI to evaluate for prolactinoma

Both normal Normal TSH, Abnormal prolactin

Hyperandrogenic anovulation

PCOS Cushing’s

Check TSH and prolactin

Normal prolactin,Abnormal TSH

Thyroid disease

No withdrawal bleed Withdrawal bleed

FSH < 5IU/L

Asherman’s Cervical stenosis

Ovarian failure

Medication

Hypothalamic amenorrhea

Chronic illness

Progestin challenge test Medroxyprogesterone acetate 10 mg daily for 10 days IF withdrawal bleed occurs – Not outflow tract obstruction IF no withdrawal bleed occurs – Estrogen/Progestin challenge test

Estrogen/Progestin challenge test Oral conjugated estrogen 0.625 – 2.5 mg daily for 35 days Medroxyprogesterone acetate 10 mg daily for 26-35 days IF no withdrawal bleed occurs – Endometrial scarring

Hysterosalpingogram or Hysteroscopy to evaluate endometrial cavity

Secondary Amenorrhea/Oligomenorrhea:

Evaluation

Evaluation of hyperandrogenism Symptoms: hirsutism, acne, alopecia, masculinization, and virilization Differential diagnosis:

Adrenal disorders: Atypical congenital adrenal hyperplasia (CAH), Cushing’s syndrome, Adrenal neoplasm

Ovarian disorders: PCOS, Ovarian neoplasms Lab: Testosterone, DHEA-S, 17α-hydroxyprogesterone

Secondary Amenorrhea/Oligomenorrhea:

Evaluation

Hormone Level Indication

Testosterone < 200 ng/dL PCOS

> 200 ng/dL Evaluate for adrenal or ovarian tumor

DHEA-S < 700 ng/dL PCOS

> 700 ng/dL Evaluate for adrenal or ovarian tumor

17α-hydroxyprogesterone

> 4 ng/mL Consider ACTH stimulation test to diagnose CAH

Treatment should be directed at… Correcting the underlying pathology Helping woman to achieve fertility (IF desired) Preventing the complications of disease process

Consequences of untreated amenorrhea/oligomenorrhea: Hypoestrogenism – Osteoporosis, Infertility Hyperestrogenism – Heart disease, Stroke, Diabetes Mellitus, Breast cancer

(controversial), Endometrial hyperplasia and Endometrial cancer

Amenorrhea/Oligomenorrhea: Management

Amenorrhea/Oligomenorrhea: Management

Diagnosis Management

Ovarian insufficiency Premature ovarian failure Postmenopausal ovarian failure

Hormone replacement therapy (HRT)

*Congenital anatomic lesions Surgical correction

*Presence of Y chromosome (i.e. AIS) Gonadectomy

*Gonadal dysgenesis (i.e. Turner syndrome) Estrogen + progestin, growth hormoneIVF (IF pregnancy desired)

Hyperprolactinemia Dopamine agonist (Bromocriptine, Cabergoline)

Functional hypothalamic amenorrhea Increase caloric intake > energy expenditure

Hypothalamic or pituitary dysfunction (non-reversible)

OCP’s, pulsatile GnRH or exogenous gonadotropins

CNS tumor Craniopharyngioma Prolactinoma

Surgical resectionMicroadenoma (< 10mm) – Dopamine agonist Macroadenoma (>10mm) – Trans-sphenoidal resection

PCOS OCP’s, weight loss, and metformin

Asherman’s syndrome Hysteroscopic lysis of adhesions

*Causes of primary amenorrhea only

Bottom Line Concepts A thorough history and physical examination as well as laboratory testing can

help narrow the diagnosis of amenorrhea.

In patients with primary amenorrhea, the presence or absence of sexual development should direct evaluation.

Constitutional delay of puberty is a diagnosis of exclusion.

The definitive method to identify hypothalamic-pituitary dysfunction is to measure FSH and prolactin levels.

If the patient has abnormal uterine development, a karyotype analysis should be performed to diagnose müllerian agenesis versus chromosomal abnormalities.

In a patient with secondary amenorrhea, pregnancy should be ruled out prior to further workup.

Treatment goals of amennorrhea and oligomenorrhea include prevention of complications such as osteoporosis, endometrial hyperplasia and heart disease; preservation of fertility; and in primary amenorrhea, progression of normal pubertal development.

References and Resources

APGO Medical Student Educational Objectives, 9th edition, (2009), Educational Topic 43 (p92-93).

Beckman & Ling: Obstetrics and Gynecology, 6th edition, (2010), Charles RB Beckmann, Frank W Ling, Barabara M Barzansky, William NP Herbert, Douglas W Laube, Roger P Smith. Chapter 35 (p315-319).

Hacker & Moore: Hacker and Moore's Essentials of Obstetrics and Gynecology, 5th edition (2009), Neville F Hacker, Joseph C Gambone, Calvin J Hobel. Chapter 32 (p355-363).

Master-Hunter T, Helman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006 Apr 15; 73(8): 1374-82.