Author: Kenneth M Bielak, MD; Chief Editor: Richard Scott Lucidi, MD, FACOG more...
Updated: Mar 02, 2016
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 apart.
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
post-menarchal 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.
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 patients
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 mid cycle 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 1012 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 911 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
The orderly progression of puberty begins with breast budding (thelarche),
accelerated growth, and menses (menarche). Adrenarche, sexual hair growth, is
independent from GnRH function and typically occurs between breast budding and
accelerated growth but may occur anywhere along the puberty timeline. Secretion
of dehydroepiandrostenedione (DHEA) initiates adrenarche. 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.) Progression of puberty requires exposure to
estrogens.
Menses occurring on a predictable cyclic pattern are associated with follicle
development and ovulation. At birth, female infants have a predetermined number
of primordial follicles. During the first trimester of pregnancy, fetal oogonia increase
in number by rapid mitosis. By the 16 to 20th week of pregnancy, up to 6 million
oogonia are present and mitosis halts. After reaching a maximum number of
oogonia cells at 20 weeks, supporting cells envelop the oocyte forming the
primordial follicle. The oocyte within the primordial follicle will enter into meiosis I,
arresting at the diplotene stage of prophase. Over the remaining 20 weeks of
pregnancy, over 4 million oocytes will undergo spontaneous atresia resulting in 2
million oocytes available at birth. Atresia continues such that only 300,000 oocytes
remain at the time of puberty. Up to 500 oocytes will ovulate during a woman
reproductive life with the remainder undergoing apoptosis. The oocytes will remain
arrested at Meiosis I unless the oocyte is chosen to progress to a primary follicle
and eventual the dominant follicle chosen for ovulation. Upon the LH surge
associated with ovulation, the oocyte is stimulated to complete meiosis 1 with
subsequent arrest at metaphase of meiosis 2. Completion of meiosis 2 occurs
after fertilization of a single sperm. 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, the GnRH pump is reactivated
under the primary control of Kisspeptin {ref 85}.
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.
Etiology
Amenorrhea after puberty 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.
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%).
Epidemiology
The incidence of primary amenorrhea in the United States is less than 1%.[21] 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 obesityrelated menstrual disorders, especially in areas where obesity is more prevalent.
[22]
Exposure to environmental toxins, namely hormonally active endocrine
disruptors, may also result in increased rates of menstrual and reproductive
disorders in endemic areas.[23]
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
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.
Women with PCOS have many long-term health issues, including higher risk of
diabetes and cardiovascular disease, that should be monitored and treated.[26, 27]
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.
Clinical Presentation
Georgetown University School of Medicine; Associate Investigator, Integrative Reproductive Medicine Unit,
Reproductive Biology and Medicine Branch, National Institutes of Child Health and Human Development,
National Institutes of Health; Private Practice, Covington and Hafkin and Associates; Director of Psychological
Support Services, Shady Grove Fertility Reproductive Science Center
Sharon N Covington, LCSW-C, BCD is a member of the following medical societies: Academy of Certified
Social Workers, American Orthopsychiatric Association, American Society for Reproductive Medicine, National
Association of Social Workers, and Society for Assisted Reproductive Technologies
Disclosure: Nothing to disclose.
Lawrence M Nelson, MD, MBA Head of Integrative Reproductive Medicine Group, Intramural Research
Program on Reproductive and Adult Endocrinology, National Institutes of Child Health and Human
Development, National Institutes of Health
Lawrence M Nelson, MD, MBA is a member of the following medical societies: American College of
Obstetricians and Gynecologists, American Society for Reproductive Medicine, Association of Professors of
Gynecology and Obstetrics, Endocrine Society, and Society for Experimental Biology and Medicine
Disclosure: Nothing to disclose.
Vaishali Popat, MD, MPH Clinical Investigator, Intramural Research Program on Reproductive and Adult
Endocrinology, National Institutes of Child Health and Human Development, National Institutes of Health
Vaishali Popat, MD, MPH is a member of the following medical societies: American College of Physicians and
Endocrine Society
Disclosure: Nothing to disclose.
Thomas Michael Price, MD Associate Professor, Division of Reproductive Endocrinology and Infertility,
Department of Obstetrics and Gynecology, Director of Reproductive Endocrinology and Infertility Fellowship
Program, Duke University Medical Center
Thomas Michael Price, MD is a member of the following medical societies: Alpha Omega Alpha, American
College of Obstetricians and Gynecologists, American Medical Association, American Society for Reproductive
Medicine, Association of Professors of Gynecology and Obstetrics, Endocrine Society, Phi Beta Kappa, Society
for Gynecologic Investigation, Society for Reproductive Endocrinology and Infertility, and South Carolina
Medical Association
Disclosure: Clinical Advisors Group Consulting fee Consulting; MEDA Corp Consulting Consulting fee
Consulting; Gerson Lehrman Group Advisor Consulting fee Consulting; Adiana Grant/research funds PI
Tamara Prodanov, MD Research Assistant, National Institutes of Child Health and Human Development,
National Institutes of Health
Disclosure: Nothing to disclose.
Shannon D Sullivan, MD, PhD Staff Physician, Department of Endocrinology, Washington Hospital Center
Shannon D Sullivan, MD, PhD is a member of the following medical societies: American Association of Clinical
Endocrinologists, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of
Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Suzanne R Trupin, MD, FACOG Clinical Professor, Department of Obstetrics and Gynecology, University of
Illinois College of Medicine at Urbana-Champaign; CEO and Owner, Women's Health Practice; CEO and
Owner, Hada Cosmetic Medicine and Midwest Surgical Center
Suzanne R Trupin, MD, FACOG is a member of the following medical societies: American Association of
Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Institute of
Ultrasound in Medicine, American Medical Association, Association of Reproductive Health Professionals,
International Society for Clinical Densitometry, and North American Menopause Society
Disclosure: Nothing to disclose.
Somya Verma, MD, Fellow in Pediatric Endocrinology, National Institutes of Child Health and Human
Development; Officer of United States Public Health Service Commissioned Corps
Disclosure: Nothing to disclose.
Wayne Wolfram, MD, MPH Associate Professor, Department of Emergency Medicine, Mercy St Vincent
Medical Center
Wayne Wolfram, MD, MPH is a member of the following medical societies: American Academy of Emergency
Medicine, American Academy of Pediatrics, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Andrea L Zuckerman, MD Assistant Professor of Obstetrics/Gynecology and Pediatrics, Tufts University
School of Medicine; Division Director, Pediatric and Adolescent Gynecology, Tufts Medical Center
Andrea L Zuckerman, MD is a member of the following medical societies: American College of Obstetricians
and Gynecologists, Association of Professors of Gynecology and Obstetrics, Massachusetts Medical Society,
North American Society for Pediatric and Adolescent Gynecology, and Society for Adolescent Medicine
Disclosure: Nothing to disclose.
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