Download PATHOPHYSIOLOGY COURSE - ENDOCRINE MODULE

PATHOPHYSIOLOGY COURSE - ENDOCRINE MODULE
DISORDERS OF THE OVARY AND AMENORRHEA
Raymond W. Ke, M.D.
Friday, December 4, 2009, 10:00-10:50a.m.
In order to understand ovarian disorders it is first necessary to establish the two primary
functions of the ovary. The human female ovary has only two responsibilities:
1. the release of mature oocytes (ovulation) and
2. production of sex hormones (steroidogenesis).
Therefore, it follows that functional disorders of the ovary will likely result in anovulation and
abnormal steroidogenesis. Since the primary unit of ovarian steroidogenesis is the egg
follicle, if ovulation is disrupted then so is hormone synthesis resulting in either amenorrhea
or dysfunctional uterine bleeding. Dysfunctional uterine bleeding should be discussed in the
context of abnormal uterine bleeding and will not be covered here.
A missed menses is common as an isolated, transient event but warrants further evaluation
and treatment when it persists and meets the diagnostic criteria of amenorrhea. Amenorrhea
simply means the absence of menstrual flow and can be classified into two categories:
1. Primary amenorrhea refers to young women or adolescents with secondary
sexual characteristics that have not experienced menarche by age 16 or, by
age 14, if there is no evidence of secondary sexual characteristics such as
breast development.
2. Secondary amenorrhea applies to previously menstruating women who have
missed the equivalent of their last three menses or have had no menses for six
months. By far, this is the more common presentation.
Menstrual Physiology
Every month for 35 years or more, during the active reproductive phase of a woman’s life and
in the absence of pregnancy, menstrual bleeding should occur. The initiation of reproductive
life is heralded by the first occurrence of uterine bleeding, called menarche, and terminated
at menopause when the major part of ovarian activity ceases. Normal human menstrual
function is dependent upon an intricate series of hormone actions linking the neuronal nuclei
of the hypothalamus to the pituitary gland which subsequently stimulates the ovaries to
produce sex steroids that act upon the endometrial lining of the uterus. Appropriately, this
pathway is known as the hypothalamic-pituitary-ovarian (HPO) axis. Along the HPO axis
there is an ingenious system of positive and negative feedback signals which allow the end
organs to communicate with the higher centers. To complicate matters, the ovary is
subjected to numerous, and as yet undefined, autocrine and paracrine actions within itself
which modulate external hormonal actions. Only with proper function of this complex
interplay do normal ovulation and menses occur.
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Uterus
Late in the menstrual cycle, the arcuate nucleus of the hypothalamus generates carefully
timed pulses of gonadotropin-releasing hormone (GnRH), which stimulates cells of the
anterior pituitary gland to produce follicle stimulating hormone (FSH) and, to a smaller extent,
luteinizing hormone (LH). In the right proportion, FSH will recruit a cohort of ovarian follicles
(eggs) to develop. At the same time, FSH/LH circulates back to the hypothalamus exerting a
negative feedback control on GnRH pulses, limiting recruitment to the initial cohort. From the
cohort of recruited ovarian follicles, a dominant follicle is selected by cycle day 7 (remember,
it is customary to designate the first day of menses as “cycle day 1” of the menstrual cycle).
It is the destiny of this one follicle to mature and proceed to ovulation, usually on cycle day
14. While achieving maturity, the dominant follicle secretes ever increasing levels of the
estrogen, estradiol, which will eventually initiate an ovulation trigger (LH surge) by a positive
feedback influence on the hypothalamus/pituitary. Increasing estradiol levels also serves to
prevent other follicles from interfering with ovulation by inhibiting FSH release through
negative feedback. Two smaller peptide hormones called inhibin and activin are also
produced by the developing follicle to assist with ovarian feedback.
Estradiol produced by the follicle, stimulates proliferative growth within the endometrial lining
of the uterus so that embryo implantation can occur later in the cycle. Once the LH trigger
has been sent by the pituitary, the ovum is released and the follicle collapses to become the
corpus luteum. The corpus luteum is a sub-organ within the ovary that produces high
amounts of progesterone and has a life-span of approximately 10 days. Progesterone
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transforms the already proliferative endometrium, increasing glandular production and
preparing for embryo implantation. If implantation does not occur, then the corpus luteum
will involute at 10 days and progesterone production is withdrawn. With progesterone
withdrawal, the endometrial lining collapses, resulting in a menses. Once progesterone and
estradiol levels have reached a nadir, the hypothalamus/pituitary escapes negative feedback
and FSH values will again rise for the subsequent cycle.
Ovulation
Menses
Progesterone
Estradiol
Day 2
8
14
20
26
Endometrial Height
A normal menses is characterized by an orderly sloughing of the entire functional
endometrium, resulting in self-limited bleeding. Only when the endometrium is first primed by
estradiol, followed by progesterone, will the uterine lining be prepared for menses. Assuming
that there is a patent outflow tract, the withdrawal of both estradiol/progesterone influences
will result in a normal menses.
Etiology of Amenorrhea
Clearly the important players in this process include the hypothalamus, pituitary, ovary, and
uterus/outflow tract. Because of the wide range of etiologies, it may be helpful to organize
them into one of these four areas.
Uterine Outflow Causes of Amenorrhea
Young women with primary amenorrhea but otherwise normal gonadal function most
commonly suffer from an anatomic etiology. Congenital absence of the vagina and uterus
(Meyer-Rokitansky-Kuster-Hauser syndrome) is the most common followed by congenital
vaginal defects and Androgen Insensitivity Syndrome (AIS).
In Meyer-Rokitansky-Kuster-Hauser syndrome, pubertal landmarks occur at the appropriate
age and secondary sexual characteristics are normal. However, the mullerian ducts fail to
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fuse leading to varying degrees of hypoplasia of the vagina, uterus, and fallopian tubes.
Most commonly, there is complete absence or a very short vaginal pouch. The incidence is
1:4000 female births and one third will have associated renal and/or skeletal anomalies.
Imperforate hymen and transverse vaginal septum cause an obstruction and accumulation of
menstrual blood. The classic presentation is monthly episodes of cyclical pain in a pubertal
girl with an associated abdominal/pelvic mass.
AIS use to be known as testicular feminization (TFM). These patients present with primary
amenorrhea, a blind vaginal pouch, absent uterus, diminished or absent pubic and axillary
hair, and normal female secondary sexual characteristics.
They are male
pseudohermaphrodites with XY karyotype. The disorder is transmitted by an X-link recessive
gene leading to a congenital absence of androgen receptors and thus they are insensitive to
the action of androgens. The male gonads, which are intra-abdominal, must be removed
after puberty because of the high risk of tumor formation.
Patients with secondary amenorrhea do not commonly present with uterine or outflow tract
obstruction. Except for the occasional case of genital mutilation or post-surgical obstruction,
these patients may have Asherman’s syndrome. This is destruction of the endometrial lining
usually following over-aggressive dilatation and curettage immediately after a pregnancy.
Pituitary Causes of Amenorrhea
A pituitary etiology for amenorrhea is usually due to a pituitary
commonly prolactin-secreting, although any adenoma may
Hyperprolactinemia leads to suppression of GnRH pulsatility as
estrogenic effect on the endometrium. It is a common cause
reproductive-age woman.
adenoma. These are
lead to amenorrhea.
well as a direct antiof amenorrhea in the
Infrequently, hypothyroidism may present as amenorrhea although more commonly as
dysfunctional uterine bleeding. It may act secondarily through hyperprolactinemia as
elevated thyrotropin-releasing hormone (TRH) stimulates prolactin release. Pituitary failure,
empty sella syndrome and CNS tumors such as craniopharyngioma are rare explanations for
amenorrhea.
Sheehan’s syndrome is a condition which causes amenorrhea due to loss of FSH/LH
secretion. It is a form of pituitary failure associated with multiple pituitary hormone deficiency
secondary to postpartum hemorrhage and shock. The degree of pituitary hypofunction is
often variable. The classic presentation is of a patient who cannot lactate after a delivery
complicated by massive post-partum hemorrhage.
Hypothalamic Causes of Amenorrhea
Hypogonadotropic hypogonadism (also referred to as hypothalamic amenorrhea) is a
diagnosis of exclusion. The possibilities include pubertal delay, anorexia nervosa, excessive
exercise, GI malabsorption, psychosocial stress, malnutrition, and organic brain disease. As
the hypothalamus is extremely sensitive to the environment, many supra-tentorial factors can
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affect the release of GnRH pulses. Since it is generally thought to be unwise for a woman to
ovulate and be fertile during times of high stress or malnutrition, one can understand the
delicacy of hypothalamic function. A classic example of hypogonadotropic hypogonadism is
that associated with anorexia nervosa. Clinically, these women present with low FSH/LH and
very low levels of estrogen production. Similarly, pubertal delay is an example of primary
hypogonadotropic hypogonadism with an identical hormone profile.
Kallmann’s syndrome is a congenital lack of GnRH neurons and is typically associated with
an inability to smell (anosmia). It is rare and occurs in males with greater frequency than
females. Hypothalamic tumors are a rare cause of primary or secondary amenorrhea.
Ovarian Causes of Amenorrhea
While an intrinsic disorder of the ovary is often associated with amenorrhea the list of
possible etiologies is rather short. It includes gonadal dysgenesis, premature ovarian failure,
surgical castration and rarely, ovarian neoplasm. It also includes polycystic ovarian
syndrome (PCOS), a condition characterized by anovulation and inappropriate androgen
secretion by the ovary. Whether PCOS is a primary derangement of the ovary, or a
combined disorder of the HPO axis, or a systemic disorder encompassing many organ
systems is yet to be fully elucidated. However, without question, this is the most common
ovarian disorder and is probably the leading cause of amenorrhea in reproductive-age
women.
Gonadal dysgenesis presents with an abnormal karyotype, either systemically or as part of a
mosaic within the germ cells themselves. The most common form of gonadal dysgenesis in
the female is Turner’s syndrome (45X0). Gonadal dysgenesis is a cause of amenorrhea
because it induces premature ovarian failure (premature menopause) as accelerated oocyte
atresia in these patients leads to early depletion of the egg store, and thus ovulation and
steroidogenesis cease. All patients with either primary or premature ovarian failure,
particularly if they are under five feet tall, should have a karyotype analysis to confirm the
diagnosis of gonadal dysgenesis and more importantly, to rule out the presence of a Y
chromosome. This is because a Y bearing gonad in the intra-abdominal position is at risk for
neoplastic transformation.
Some premature ovarian failure patients are thought to suffer from an autoimmune etiology.
This is often part of a multi-glandular autoimmune endocrinopathy and often ovarian failure is
the first endocrine system to present. In these patients, yearly screening for thyroid,
parathyroid, adrenal, etc. dysfunction is important. Patients suffering with ovarian failure or
gonadal dysgenesis will require indefinite hormone replacement therapy since they have no
endogenous ovarian estrogen production. Without therapy, long term estrogen deprivation
results in osteoporosis and accelerated risk for cardiovascular disease. In addition to
gonadal dysgenesis and autoimmunity, there are other forms of ovarian failure such as viral
(mumps oophoritis) and post-radiotherapy.
Polycystic Ovarian Syndrome
PCOS classically presents as anovulation, hirsutism and obesity. However, only 70% of
patients with PCOS will present with all three symptoms. The classic radiological
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appearance of a polycystic ovary on transvaginal ultrasound is only readily apparent in 60%
of patients. Anovulation does appear to be the most consistent symptom.
The pathophysiology of PCOS is not clear and the initial insult has not been identified.
PCOS involves a cycle of events with the inability to ovulate leading to the production of
excess androgens by the ovary. The androgens are converted to estrogens by peripheral
adipose tissue providing PCOS patients with a rich estrogenic environment. Unfortunately,
without ovulation, there is no progesterone effect and thus the patient rarely menstruates.
The estrogenic milieu also induces more LH to be secreted by the pituitary which promotes
further anovulation and androgen production by the ovary thereby worsening the condition.
Hirsutism
Insulin
resistance
and
obesity
Increased
androgens
Increased LH
PCOS
Anovulation
Anovulation
Amenorrhea
Acyclic estrogen
PCOS patients need to be treated and counseled carefully. Chronic anovulation and
amenorrhea may often lead to endometrial hyperplasia and even endometrial carcinoma
because the proliferating lining is not being shed. This may even occur in young patients
under the age of 25. Secondly, while the hyperandrogenism experienced by these patients is
often moderate, hirsutism can be a debilitating complaint that leads often to social isolation
and distress. Lastly, PCOS patients have an increased risk of other metabolic diseases such
as diabetes and need to be counseled regarding their risk of glucose intolerance and
possible accelerated cardiovascular disease. Whether this is linked to their obesity, a high
androgen level, or a striking association with insulin resistance is still not known.
Evaluation of Amenorrhea
Clearly there are multiple etiologies encompassing almost all the organ systems in the body.
Therefore, a thorough history is vital and should direct the clinician to appropriate
investigations. However, for all patients with amenorrhea an algorithm for evaluation starts
with four investigations.
1. Pregnancy Test. Pregnancy is still the leading reason for amenorrhea in the
reproductive age group. In the evaluation of this symptomology, pregnancy should
always be assumed until effectively ruled out. Modern immunoassays for the ß-hCG
molecule are highly sensitive pregnancy tests and should be performed on every patient
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2.
Physical Exam. While a thorough exam goes without question, the clinician should be
aware of two areas, particularly in the adolescent with primary amenorrhea. The first is
to stage the patient’s breast development.
Abnorm al bre ast
developme nt
Tanne r sta ge 1 or 2
-- m ea sure FSH
FSH
high
FSH
low
Gonada l fa ilure
or dysgene sis
CT sca n
or MRI
Abnorm al -trea t a ccordingly
Norma l -hypotha la mic or pituita ry
puberta l dela y
If an adolescent exhibits only Tanner stage I or II breast development, she is not likely
to have been exposed to significant circulating levels of estradiol. An elevated FSH
measurement at this time indicates ovarian failure and gonadal dysgenesis is the likely
diagnosis.
A low or normal FSH would be inappropriate given the relative
hypoestrogenism and suggests a pituitary or hypothalamic etiology. Imaging of the
head is required to rule out a serious neoplastic origin. Assuming the CT scan is normal
and serum TSH and prolactin are normal, then this patient should be treated as pubertal
delay.
The second step is to perform a vaginal examination. This needs to be performed
carefully in a virginal female and is best left to an experienced pediatric gynecologist in
the young. If the physical exam reveals an absent vagina or a vagina that ends in a
blind pouch without evidence of cervix, then the presence of pubic and axillary hair
should be evaluated. If axillary and pubic hair is well developed, then the patient has
mullerian tract agenesis or Rokitansky-Kuster-Hauser syndrome. However, if there is a
lack of pubic hair in this patient, AIS is suspected. This can be confirmed by
demonstrating a circulating testosterone level in the normal male range.
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Abnormal
or
absent
vagina
Pubic hair
present
Pubic hair
absent
Imperforate hymen,
Trans. vaginal septum,
or
Rokitansky
Androgen
insensitivity
syndrome
3. Thyroid stimulating hormone (TSH)/Prolactin. Hyperprolactinemia affects 5-10% of
amenorrheic patients and often presents with galactorrhea. It should be first evaluated
with a CT scan or MRI of the head to look for a large pituitary adenoma. Presently, even
large macroadenomas of the pituitary can be very successfully treated with medical
therapy. In the absence of an adenoma many medications, especially psychotropic
drugs, may elevate prolactin levels and cause amenorrhea and even galactorrhea.
Abnormal
TSH/prolactin
Hyperprolactinemia
High TSHhypothyroidism
Suppressed TSHhyperthyroidism
CT scan or MRI
Normalidiopathic hyperprolactinemia
Abnormaltreat accordingly
While thyroid disease is an uncommon direct etiology for amenorrhea (< 3%), the serum
TSH level is a useful screen because hypothyroidism can be a common cause of
hyperprolactinemia and because it is relatively inexpensive. In addition, the treatment
of hypothyroidism is simple and very gratifying to both patient and clinician. A
suppressed TSH level indicates a hyperthyroid condition and deserves further
endocrinology workup.
4.
Progestin Challenge Test. In the woman of reproductive age who is experiencing
secondary amenorrhea the clinician needs to assess the estrogen level in the patient.
While one can certainly draw a blood test, a much more useful evaluation is to perform
the progestin challenge test. Not unlike evaluating breast development, the progestin
challenge test is an effective bioassay for not only endogenous estrogen but for the
presence of a patent uterus and lower outflow tract.
Remember that in order for a woman to menstruate normally, her endometrium must
first be primed with estrogen and then be exposed to progesterone (or progestin)
Disorders of the Ovary and Amenorrhea (Female Gonadal Disorders)
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followed by withdrawal of both hormones. The progestin challenge test is given to an
amenorrheic woman with a negative pregnancy test by administering
medroxyprogesterone acetate (Provera) 10 mg/day for 10 days. If the patient has a
menses within 7 days after the Provera then she has a positive result. It implies that her
endometrium has been primed by adequate circulating levels of estrogen. It also
implies that the uterus and lower outflow tract is intact. If ovarian estrogen production is
intact, the diagnosis of polycystic ovarian syndrome is made. Supporting evidence may
include obesity, hirsutism, and other features of hyperandrogenism.
Progestin Challenge Test
After administration of progestin, wait for onset of menses
Positive menses
Negative menses
Anovulation (PCOS)
Estrogen+progestin challenge
Positive menses
Negative menses
FSH
Uterine/outflow problem
FSH low or normal
FSH high
CT or MRI scan
Premature ovarian failure
Abnormal -treat accordingly
Normal -Hypogonadotropic
Hypogonadism
If the patient fails to experience a menses following progestin withdrawal, then she
either has:
1. inadequate levels of circulating estradiol or
2. an obstructed outflow tract.
The next step would be to provide the woman with an estrogen/progestin challenge
(conjugated estrogens 1.25 mg/day for 25 days combined with Provera 10 mg/day for
the last 10 days). If she again fails to have a menses then the reproductive tract is
either absent or obstructed. If, however, she does have a menses, then again the
cause of inadequate circulating estradiol levels needs to be assessed. Therefore, an
FSH value is measured with a high level implying premature ovarian failure. A low or
normal FSH value again implies a pituitary or hypothalamic lesion and imaging of the
brain again has to be undertaken. A normal brain image in this instance suggests that
the woman has hypogonadotropic hypogonadism.
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Treatment of Amenorrhea
The treatment of amenorrhea falls under three principles:
1. What is the etiology? While amenorrhea itself is not a cause of morbidity, it is usually a
symptom of an underlying pathophysiology that needs to be treated. Thus, the treatment
of amenorrhea has to be tailored according to the etiology.
2. All pathological causes of amenorrhea need to be treated. If the patient is
amenorrheic because she is taking hormone replacement or oral contraceptives, that is
not, in itself, harmful. Apart from this scenario and pregnancy, however, most
pathological causes of amenorrhea have severe consequences. Depending on the
cause, they include lack of secondary sexual characteristics, identification with a feminine
gender role, endometrial neoplasia, central nervous system neoplasia, other
endocrinopathies, osteoporosis, cardiovascular disease, diabetes, etc.
Treatment
therefore should not be unduly delayed. Most treatments are aimed at restoring regular
menses or physiologic hormone replacement, even if the underlying etiology has not been
corrected.
3. Is fertility an issue? For those patients that wish to conceive, clearly the first goal would
be to initiate ovulation induction. In some cases, such as hyperprolactinemia, medical or
surgical correction of the underlying problem will be the only therapy required. For PCOS,
the patients will require some form of ovulation induction with medications such as
clomiphene citrate but others may require more intensive assisted reproduction such as in
vitro fertilization (IVF). Pregnancy is difficult but not impossible in women with ovarian
failure when her oocytes have been depleted. Donor oocyte in vitro fertilization
techniques, while expensive, offer these women the opportunity for pregnancy. Third
party parenting is indicated for women with an absent uterus.
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References
1. Padilla SL, McDonough PG. Sexual abnormalities. In: Unwanted Hair-Ancestral Curse or
Gland Disorder. Greenblatt RB ed. New York: Parthenon Press, 1985.
2. Chiazze L, Brayer FT, Micisco JJ, Parker MP, Duffy BJ. The length and variability of the
human menstrual cycle. JAMA 203:337, 1968.
3. Reindollar RH, Byrd JR, McDonough PG. Delayed sexual development-a study of 252
patients. Am J Obstet Gynecol 140:371-380, 1981.
4. Griffin JE, Wilson JD. The syndromes of androgen resistance. N Engl J Med 302:198204, 1980.
5. Shangold M, Tomai T, Chin S, Zinamin M, Cook J, Simon J. Factors associated with
withdrawal bleeding following administration of oral micronized progesterone in women
with secondary amenorrhea. Fertil Steril 56:1040-1047, 1992.
6. Vollman RF. The menstrual cycle. Philadelphia:WB Saunders, 1977.
7. Rarick LD, Shangold M, Ahmed SW. Cervical mucus and serum estradiol as predictors of
response to progestin challenge. Fertil Steril 54:353-359, 1990.
8. Frisch RE. Body fat, menarche, and reproductive ability.Semin Reprod Endocrinol 3:4557, 1985.
Suggested Reading
1. McDonough PG. Amenorrhea - etiology approach to diagnosis. Fertil Steril 30:1 - 15,
1978.
2. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility. Seventh edition.
Chap. 11, 12. Baltimore: Lippincott, Williams & Wilkins. 2005.
3. Yen SSC, Jaffe RB (eds). Reproductive Endocrinology. Third edition. Chap. 6, 17,18.
Philadelphia: W.B.Saunders. 1991.
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