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By Medifit Education




Amenorrhea (uh-men-o-REE-uh) is the absence of menstruation — one or more missed menstrual periods. Women who have missed at least three menstrual periods in a row have amenorrhea, as do girls who haven’t begun menstruation by age 15.

The most common cause of amenorrhea is pregnancy. Other causes of amenorrhea include problems with the reproductive organs or with the glands that help regulate hormone levels. Treatment of the underlying condition often resolves amenorrhea.



Amenorrhea can result because of an abnormality in the hypothalamic-pituitary-ovarian axis, anatomical abnormalities of the genital tract, or functional causes.

Hypothalamic causes

Amenorrhea can result because of an abnormality in the hypothalamic-pituitary-ovarian axis, anatomical abnormalities of the genital tract, or functional causes.

Hypothalamic causes

  • Craniopharyngioma (a brain tumor near the pituitary gland)
  • Teratoma (a tumor made up of a mixture of tissues)
  • Sarcoidosis (a chronic disease of unknown cause characterized by the formation of nodules in different parts of the body)
  • Kallmann syndrome (deficiency of gonadotropins, which are hormones capable of promoting growth and function of reproductive organs)
  • Nutritional deficiency
  • Low body weight or growth delay

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Pituitary causes

  • Prolactinemia (high blood levels of prolactin, a hormone that stimulates secretion of milk from the breasts during breastfeeding) – possibly caused by prolactinoma (a tumor of the pituitary gland secreting the hormone prolactin)
  • Other pituitary tumors (for example, Cushing syndrome, acromegaly, orthyroid-stimulating hormone)
  • Postpartum pituitary necrosis (death of pituitary cells after a woman delivers a baby)
  • Autoimmune hypophysitis (cells of the pituitary gland destroyed by the body’s own defense system)
  • Pituitary radiation
  • Sarcoidosis

Ovarian causes

  • Anovulation (lack of the release of an egg)
  • Hyperandrogenemia (high blood levels of male hormones)
  • Polycystic ovary syndrome (hormonal disorder affecting women of reproductive age)
  • Premature ovarian failure
  • Turner syndrome (a genetic disorder characterized by underdeveloped ovaries, absence of menstrual onset, and short stature)
  • Pure gonadal dysgenesis (defective development of the ovary)
  • Autoimmune oophoritis (cells of the ovaries destroyed by the body’s own defense system)
  • Fragile X premutation
  • Radiation or chemotherapy
  • galactose (an inherited disorder in which galactose, a type of sugar, accumulates in the blood)
  • Anatomical abnormalities of the genital tract
  • Intrauterine adhesions (the opposing surfaces of the uterine cavity stick together)
  • Imperforate hymen (a hymen in which there is no opening, the membrane completely closes off the vagina)
  • Transverse vaginal septum (a dividing wall or membrane in the vagina)
  • Aplasia (absence of an organ or tissue) of the vagina, the cervix, or the uterus

Functional causes

  • Anorexia/bulimia
  • Chronic diseases (for example, tuberculosis)
  • Excessive weight gain or weight loss
  • Malnutrition
  • Depression or other psychiatric disorders
  • Recreational drug abuse
  • Psychotropic drug use (drugs prescribed to stabilize or improve mood, mental status, or behavior)
  • Excessive stress
  • Excessive exercise
  • Cycle suppression with systemic hormonal contraceptive (birth control) pills

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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 mid cycle surge of LH. E2 promotes uterine endometrial gland growth, which allows for future implantation.

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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.


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.


The main sign of amenorrhea is the absence of menstrual periods. Depending on the cause of amenorrhea, you might experience other signs or symptoms along with the absence of periods, such as:

  • Milky nipple discharge
  • Hair loss
  • Headache
  • Vision changes
  • Excess facial hair
  • Pelvic pain
  • Acne

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The woman’s period starts, but then ceases to occur. This can be physiologic (natural, normal), as during pregnancy or lactation, or pathologic, when caused by something that is medically harmful. In most countries doctors define this type as an absence of menstruation for at least six months in a female you used to have normal periods.


It is usually caused by some gynecological disorder, or severe underweight. If a woman’s BMI (body mass index) falls below 19, her risk of developing amenorrhea increases significantly. Serious weight loss may be caused by a physical illness or an eating disorder.


According to the NHS, about 3% of females are affected. A significant number of competitive long-distance runners and professional ballet dancers are affected.


Women’s periods may also stop as a result of severe emotional upheaval or extreme stress.


Some medications, such as progesterone-only contraceptives, as well as a number of psychiatric drugs may result in the absence of menstruation.


Amenorrhea can also be a consequence of a long-term illness, such as polycystic ovary syndrome, or premature ovarian failure.


If the absent periods are caused by lifestyle factors, such as excessive exercise – a change of exercise plan, or even adjusting one’s diet may help bring the periods back. Excessive weight loss may require a professionally supervised weight gain regime. Those with some type of eating disorder will be under the supervision of a psychiatrist and also a nutritionist/dietician.


Some people with an underactive thyroid may experience loss of menstruation. Treatment with thyroxine, a thyroid hormone, will usually bring them back.


People who become overweight from polycystic ovary syndrome may find that losing weight helps.


If the doctor determines that the amenorrhea was caused by emotional or mental stress, psychological therapy may be ordered.


Periods may come back if a patient with premature ovary failure receives HRT (hormone replacement therapy).


If the patient’s genitals have not developed as they should, surgery may be needed.


By Medifit Education