Dysfunctional uterine bleeding

GnRH is released from the hypothalamus in pulses which vary depending on the phase in the menstrual cycle.

GnRH pulse frequency is approximately once per 90 min in the follicular phase.

The pulses are less frequent in the luteal phase, occurring approximately once in 4 h.

GnRH acts on the anterior pituitary through the hypothalamohypophyseal portal system to cause release of the gonadotropins - LH and FSH. These in turn act on the ovary to cause release of estrogen and progesterone.

Disorders that slow GnRH pulsatility, such as anorexia nervosa, result in failure of secretion of pituitary gonadotropins (LH and FSH) and a state of hypogonadal hypogonadism with failure of follicular development and amenorrhea.

Less severe reductions in GnRH pulse amplitude and frequency result in diminished FSH and LH with some follicular stimulation but not enough to result in ovulation but estradiol is secreted. This may occur in stress, hyperprolactinemia, excessive exercise or may be idiopathic.

An understanding of the normal cyclic fluctuations of the 2 gonadotropins (i.e., luteinizing hormone [LH], follicle-stimulating hormone [FSH]) and the primary female reproductive hormones (i.e., estrogen, progesterone) helps clarify the derangements associated with anovulation.

With anovulation, estrogen levels rise as usual in the early phase of the cycle and because there is no ovulation, a corpus luteum never forms and progesterone is not produced.

There is a continuous unopposed estrogenic stimulation of the endometrium. Theendometrium as a result moves into a hyperproliferative state, ultimately outgrowing its blood supply.

This leads to irregular sloughing of the endometrium and excessive bleeding from spiral arteries that have not undergone physiological senescence.

The normal cycle is 28-29 days (range of 21-35d).

Normal menstrual flow lasts 3-7days.

Average total blood loss of 25-69 mL. Flow longer than 7 days and blood loss exceeding 80 mL is considered abnormal.

The normal cycle is characterized by sequential growth, maturation and eventual sloughing of the endometrial mucosa.

This is produced by the cyclic release of estrogen and progesterone from the ovary and is orchestrated by the HPO axis.

FSH stimulates ovarian follicle development and the subsequent production of estrogen, primarily estradiol.

The endometrium, under the influence of estrogen, undergoes proliferation.

LH levels abruptly peak on day 12 or 13 in positive response to rising estrogen level. The LH surge stimulates-

• Ovulation (on or about day 14), and
• Conversion of the ovulatory follicle to corpus luteum, which is responsible for progesterone production.

Under the influence of progesterone, the endometrium is converted to a secretory state in preparation for implantation if fertilization of the ovum should occur. Progesterone is produced only if ovulation occurs.

As LH levels drop (in the absence of fertilization, production of human chorionic gonadotropin [HCG] by the developing conceptus does not occur), the corpus luteum regresses, estrogen and progesterone levels plummet, and the endometrium deteriorates and is sloughed.

Bleeding occurs cyclically.

There is an increased rate of blood loss resulting from vasodilatation of the vessels supplying the endometrium due to decreased vascular tone, and prostaglandins have been strongly implicated.

Therefore, these women lose blood at rates about 3 times faster than women with normal menses.

In women with normal blood flow the order of production of prostaglandins by the secretory endothelium is PGF2α/PGE2/PGD.

Increased amount of PGI (prostacyclin) are produced in the myometrium of DUB patients due to increased production of endoperoxidases.

Menorrhagia: heavy bleeding, including prolonged menstrual periods (bleeding that lasts more than 7 days), or excessive bleeding (blood loss of greater than 80 ml per period) during a normal length period.Regular cycles, prolonged duration, excessive flow.

Metrorrhagia: bleeding at irregular intervals, particularly between expected menstrual periods. Frequent and irregular cycles.

Menometrorrhagia: prolonged or excessive uterine bleeding that occurs irregularly and more frequently than normal. Irregular, prolonged, excessive.

Hypermenorrhea: a menstrual period with excessively heavy flow. Regular, normal duration, excessive flow.

Polymenorrhea: frequent regular cycles that is shorter than 21 days.

Oligomenorrhea: Infrequent cycles. Uterine bleeding at regular intervals from 35 days to 6 months.

Amenorrhea: primary amenorrhea is the failure of menses to occur by age 16, in the presence of normal growth and secondary sexual characteristics. Secondary amenorrhea is the cessation of uterine bleeding in a post-menarchial girl or a reproductive-aged woman for > 6 months.

Postmenopausal bleeding: uterine bleeding that occurs more than 1 year after the last menses in a woman with ovarian failure.

COCs contain both estrogen and progestins.

With COCs pills, bleeding usually is controlled within the first 24 hours, as the overgrown endometrium becomes pseudodecidualized, reestablish predictable bleeding patterns, decrease menstrual flow, and lower the risk of anemia.

Additional benefits, include decreased dysmenorrhea and ovarian cancer prophylaxis.

Tablets or injections

E.g. IV Premarin

Useful for acute bleeding.

25 mg IV q4 hours(every 4 hours) until bleeding slows.

Causes nausea, breast tenderness.

Give slowly or can cause vasovagal reaction or LOC.

Must give progestins for 7- 10 days after and then will have withdrawal bleed or start continuous OCPs.

Mainly indicated in patients with anovulatory bleeding to reverse the effects of estrogen mediated endometrial proliferation and induce endometrial maturation.

Cyclic progestin for 10 days per month using medroxyprogesterone acetate (10 mg/d) or norethindrone acetate (2.5-5 mg/d) provides predictable uterine withdrawal bleeding, but not contraception.

Blocks formation of prostacyclin, an antagonist of thromboxane, which is a substance that accelerates platelet aggregation and initiates coagulation. Prostacyclin is produced in increased amounts in menorrhagic endometrium. NSAIDS thus effectively decrease uterine blood flow.

Examples include Mefenamic acid and Naproxen.

Induces postreceptor effects, which suppress gonadotropin release, with resultant hypogonadism resulting in amenorrhea, thus breaking cycle of abnormal bleeding in anovulatory patients.

Should not be used for more than 6months without adding a back-up therapy.

Prolonged use is associated with osteoporosis and other postmenopausal side effects.

At the onset of menses, secretory endometrium contains a high concentration of plasminogen activator.

A reduction in menstrual blood loss has been demonstrated in some ovulatory patients taking ε-aminocaproic acid (EACA) or aminomethylcyclohexane-carboxylic acid (AMCHA) tranexamic acid, both potent antifibrinolytics.

Androgens have been used to treat mild to moderate bleeding, particularly ovulatory DUB, they function by altering endometrial tissue so that it becomes inactive and atrophic.

They offer no real advantage over other regimen, can cause irreversible signs of masculinization.

They are seldom used again.

They might stimulate erythropoiesis and clotting deficiency.

Examples are Danazol (Danocrine) and Isoxazole, derivative of 12 alpha-ethinyl testosterone