Abnormal uterine bleeding at 40+ years of age

• endometrial polyps
• submucous fibroids
• endometritis
• endometrial scarring (Asherman's syndrome)
  endometrial hyperplasia
  • simple (cystic stromal and glandular)
    complex
    • adenomatous
    • atypical adenomatous
• endometrial carcinoma
• endometrial sarcoma
  postmenopausal dysfunctional
  • atrophic
    estrogen replacement related
    • withdrawal
    • breakthrough
• tamoxifen therapy related

Under 40 years of age, the incidence of uterine cancer is quite low so that endometrial sampling by biopsy or D&C is not always the first step in a workup. Over the age of 40 and for high risk patients (polycystic ovarian disease, patients with obesity and hypertension, and anovulation) over the age of 35, all patients with abnormal bleeding should have endometrial sampling. Also there is more common occurrence of mechanical bleeding causes such as endometrial polyps or uterine fibroids in this age category. Abnormal uterine bleeding would be defined as any menstrual bleeding longer than 7 days of menses and any menses less than 23 days apart. Volume of flow also may be abnormal but it is very to measure. History alone is not always accurate. When it has been measured, a blood flow of more than 120 mls (about 4 oz) per menses is considered excessive and would be classified as abnormal.

Goals

Any abnormal bleeding over the age of 40 or over the age of 35 in high risk patients should be primarily investigated by evaluation for mechanical causes or cancer. Usually an endometrial biopsy is performed, although imaging techniques such as ultrasound or hysterosongraphy can also be used. Once endometrial cancer is ruled out by biopsy, the patient can be treated with hormonal therapy under the presumption of endocrinological causes of the abnormal bleeding. If there is no response to this however, a direct evaluation of the endometrium such as hysteroscopy should be performed because of the high incidence of polyps and fibroids that disturb the endometrial cavity and may produce abnormal bleeding.

Abnormal uterine bleeding - menarche to menopause

• hypothyroidism
• hyperthyroidism
• drug induced/medication side effects (coumadin, ASA, steroids)
  coagulation disorders
  • thrombocytopenia
  • thrombocytopenia from septicemia and chronic infection
  • immunologic thrombocytopenia
  • diminished platelet production or increased destruction
  • hereditary clotting factor abnormalities
  • factor VIII deficiency (von Willibrand's disease)
  • factor XI deficiency (Rosenthal's syndrome)
  • factor V deficiency (Owren's disease)
  • factor VII deficiency
  • factor X deficiency (Stuart factor deficiency)
  • prothrombin deficiency and dysfibrinogenemia
    multiple factor deficiencies
    • liver cirrhosis
    • hepatitis
  • trauma/foreign bodies
    infection
    • severe vaginal infection (trichomonas, bacterial vaginitis, yeast)
    • cervicitis

contraceptive associated
• depomedroxyprogesterone associated
• combined oral contraceptive associated
• progestin only OCP
• progestin implant
• postpill anovulation/galactorrhea
increased prolactin
• pituitary prolactinoma
• hyperprolactinemia
• other pituitary tumors
• empty sella syndrome
• growth hormone excess - acromegally
• ACTH excess - Cushing's disease
• Nelson's syndrome
• pseudotumor cerebri
• chronic renal failure/hemodialysis
• persistant postpartum amenorrhea-galactorrhea
• spontaneous amenorrhea-galactorrhea
• liver cirrhosis
• hepatitis
• chronic systemic disease

• stress-related
• polycystic ovarian syndrome
• acanthosis nigricans/hyperandrogenism/insulin resistance
• adrenogenital syndrome
• Cushing's syndrome
• hypothyroidism
• obesity

Most women will have at least one, possibly more, episodes of abnormal uterine bleeding, unrelated to pregnancy, during their reproductive years. Most events are isolated and infrequent and menses usually revert to normal within one or two cycles.

Goals

If abnormal bleeding patterns persist beyond one or two cycles, then investigation is warranted. Any endocrine abnormalities or medications or general metabolic diseases that interfere with the normal ovulation sequence can produce abnormal uterine bleeding. Search for the multiple possible causes of this "dysfunctional" bleeding is primarily by history and physical exam along with targeted laboratory studies. Often a trial of hormonal therapy is given.

Never a menstrual period and delayed sexual development

primary amenorrhea without breast development

CNS lesions
• congenital CNS defects
• prolactinoma
• other pituitary adenomas
• malignant pituitary tumor
• craniopharyngioma
• hypothalamic hypogonadism with anosmia (Kallmann's syndrome)
• deficiency of GnRH
• hypopituitarism
• postsurgical hypopituitarism
• Laurence-Moon-Biedl syndrome
• Prader-Willi syndrome
• primary hypothyroidism
• congenital adrenal hyperplasia
• Cushing's syndrome
• gastrointestinal malabsorption
• physiologic delay
• exercise amenorrhea
• weight loss/anorexia
• (see also hypothalamic amenorrhea)

• gonadal dysgenesis 45 XO (Turner's syndrome)
• gonadal dysgenesis 46 XY (Swyer syndrome)
  gonadal dysgenesis 46 XX
  • familial gonadal dysgenesis
  • 17-à-hydroxylase deficiency
• galactosemia
• ataxia telangiectasia
• myotonia dystrophica
• autoimmune disorders
• chemotherapy/radiation therapy (ovarian cytotoxicity)
• resistant ovary syndrome

This category of problems is relatively rare and indicates a major abnormality of the normal developmental process. In this case the problem is not so much the absence of menses but the delayed progress of sexual development. Something has gone wrong at the brain level in failing to initiate the normal sequence of sexual development.

Goals

Multiple medical diseases and endocrinologic abnormalities can be associated with this problem; many having to do with the brain or central nervous system Thorough history and physical evaluation along with quite a few endocrinological and other laboratory studies is usually indicated. Imaging studies such as MRI, are used to search for tumor or vascular lesions.

Never a menstrual period and normal sexual development

primary amenorrhea with normal breast/body development

• mullerian agenesis
• imperforate hymen
• transverse vaginal septum
• vaginal agenesis (Mayer-Rokitansky-Kuster-Hauser Syndrome)
• testicular feminization
• intersexuality
• mosaicism
• polycystic ovarian syndrome
• adrenal hyperplasia or tumor (androgen producing)
• hypothyroidism
• exercise amenorrhea
• any other anovulation cause occuring just before menarche

This category of problems also occurs very infrequently. A major issue that arises is at what age should the first menstrual period have occurred. A rule of thumb is that if menses has not occurred within 2 years of breast development, that is abnormal. Thus a woman at 16 years of age who began breast development at 13 years old would be classified as having primary amenorrhea whereas a woman who is 17 years of age who began breast development later at the age of 16 would still not fall into this category.

Goals

Many of the problems in this category are based on anatomical congenital anomalies. Therefore a good physical and pelvic exam are important in the diagnostic workup as well as imaging studies. This is differentiated from the category of amenorrhea with delayed sexual development in which multiple hormonal studies, are needed because of the lack of development.

Stopped menstrual periods or infrequent menses

secondary amenorrhea or oligomenorrhea - non pregnant

CNS lesions
• craniopharyngioma
• metastatic tumors
• sarcoidosis
• Wegner's granulomatosis
• histiocytosis
• syphylitic gumma
• tuberculoma
• carotid artery aneurysm
• hydrocephalus
• empty sella syndrome
• pituitary stalk section
• postpartum pituitary necrosis (Sheehan's syndrome)
• stress-induced, psychogenic amenorrhea
• anorexia nervosa
• buleimia
• exercise amenorrhea
• pseudocyesis
• drug-induced
• idiopathic

Ovarian
premature ovarian failure
• autoimmune disease
• chemotherapy
• hypoadrenalism
• ovarian dysgenesis
• resistant ovary syndrome
• pseudo-ovulation
• ovarian destruction
• ovarian tumors
• endometriosis
• post surgical
Ectopic gonadotropin production
• ovarian choriocarcinoma
• ovarian dysgerminoma
• liver hepatoblastoma

increased prolactin
• pituitary prolactinoma (micro or macroadenoma)
• hyperprolactinemia - medication induced
  • amitriptyline (Elavil®)
  • androgens (testosterone)
  • anesthetics (usually post surgical)
  • chlorpromazine (Thorazine®)
  • cimetadine (Tagamet®)
  • estrogens
  • fluphenazine
  • haloperidol (Haldol®)
  • metoclopramide (Reglan®)
  • monoamine oxidase inhibitors (Nardil®, Parmate®)
  • opiates (codiene, pain pills, morphine)
• other pituitary tumors
• empty sella syndrome
• growth hormone excess - acromegally
• ACTH excess - Cushing's disease
• Nelson's syndrome
• pseudotumor cerebri
• hypothyroidism
• chronic renal failure
• persistant postpartum amenorrhea-galactorrhea
• spontaneous amenorrhea-galactorrhea
• postpill anovulation/galactorrhea
• polycystic ovarian syndrome
• acanthosis nigricans/hyperandrogenism/insulin resistance
• adrenogenital syndrome
• Cushing's syndrome
• hypothyroidism
• obesity
• chronic systemic disease
• intrauterine scarring (Asherman's syndrome)

Pregnancy is the most common cause of cessation of menses and therefore should be ruled out before placing a problem in this category. Unfortunately there are other problems that can frequently delay menses or cause infrequent menses in women and this category of problems still presents frequently. Of the many other causes listed above. stress-induced amenorrhea and polycystic ovarian disease are the most common. The others tend to be more infrequent.

Goals

This category is best divided into those associated with low gonadatropins (FSH and LH), normal gonadatropins or high gonadatropin levels. If the gonadatropins levels are in normal ranges diagnoses should be directed toward whether estrogen levels are low or not. Normal to high estrogen levels often can be determined clinically. Copious, clear cervical mucous, ferning of cervical mucous, vaginal stripe on endometrial ultrasound of 6mm or greater, or withdrawal bleeding to a progestin challenge indicate estrogens are being produced. The different gonadatropins levels give an indication of possible etiology of the problem while the estrogen levels are helpful in determining treatment for the problem. Patients with low estrogen levels will probably need estrogen supplementation in order to straighten out any bleeding while patients with normal or high estrogen levels will periodically need some form of progestin induced withdrawal bleed in order not to have more severe abnormal uterine bleeding in the future.

Premenstrual mood disturbances

• menstrual distress
• anxiety/stress reaction with cyclic exacerbation
• depression with cyclic exacerbation
• premenstrual syndrome

Some degree of mood affectation can occur in most women just before their menses. Usually this does not become a severe disturbance,but in approximately 5% of women, those disturbances are severe enough to seek medical attention.

Goals

Many underlying psychologic states with mood problems can be worsened premenstrually. It is critical to differentiate ongoing psychologic problems such as depression and anxiety/stress reactions that are worsened premenstrually, versus a "pure" premenstrual syndrome. In the former instance treatment must be directed toward the underlying mood disturbance whereas in the later instance hormonal therapy may be more effective. Psychologic mood evaluation questionaires are usually administered in the first week after menses and also about 4-7 days prior to the next menses. These should show a 50% or greater worsening in the premenstrual phase. A prospective symptom calendar over one or more months should show definitely lower symptom intensity in the first part of the menstrual cycle.