Ovulatory dysfunction is comprised of a variety of different
conditions that each result in the same outcome - either
irregular ovulation or the total lack
of ovulation. The major symptom of ovulatory dysfunction is a
history of irregular menstrual cycles. Most ovulatory menstrual
cycles are regular, occurring every 27-30 days or so, and are
accompanied by some mild uterine cramping. Most ovulatory patients
also experience some breast swelling and/or tenderness in the few
days leading up to the onset of menstrual bleeding, and many
patients may also have some mid-cycle discomfort (“mittleschmertz”)
that occurs around the time of ovulation. Women with ovulatory
dysfunction, on the other hand, frequently have very irregular
cycles, ranging from 30-90+ days in length, rare menstrual cramping,
and no mid-cycle discomfort. They may have other symptoms as well,
such as a milky breast discharge and/or an increase in hair growth –
predominantly on their face, chest, or back.
A
patient’s clinical presentation and laboratory evaluation will help
the physician determine the cause of the ovulation disorder. The
initial workup of ovulatory dysfunction includes an evaluation of thyroid function and a measurement of
the pituitary hormone
prolactin. It is important that the
prolactin determination be performed on a blood sample obtained
early in the morning while fasting. The most common ovulation
disorders include hyperprolactinemia, hypothyroidism, polycystic
ovarian syndrome, hypothalamic dysfunction, and impending
ovarian failure.
Women who have elevated prolactin levels leading to ovulatory
dysfunction initially need an evaluation of the pituitary gland to
exclude a tumor as the source of the excess prolactin production.
Pituitary tumors responsible for excessive prolactin production are
essentially always benign, and they are usually treated with a
category of medications called dopamine agonists. The most common
medications are bromocriptine (ParlodelTM) and
cabergoline (DostinexTM). Patients with thyroid
disorders – most commonly hypothyroidism - are typically treated
with thyroid replacement therapy.
Hypothalamic dysfunction or hypothalamic amenorrhea is an uncommon
cause of ovulatory dysfunction. Oftentimes women with this
condition are thin with a low percentage of body fat and have almost
complete absence of menses when not on hormonal contraception or
replacement. This can be due to excessive exercise or conditions
such as anorexia nervosa, but is often present without an obvious
cause. The evaluation of women with hypothalamic amenorrhea
includes laboratory testing for the pituitary hormones FSH and LH,
which are either in the normal range or low, as well as a serum
estradiol level which is typically less than 10pg/ml. On
ultrasound evaluation, women with hypothalamic amenorrhea often have
a very thin uterine lining and their ovaries may be small as well.
Women with hypothalamic amenorrhea who are given progesterone to
induce menses typically will not experience a period due to the
absence of an estrogen-primed uterine lining. Women with
hypothalamic amenorrhea will occasionally respond to clomiphene
citrate for ovulation induction, but often need treatment with human
menopausal gonadotropins (see gonadotropin stimulation).
Impending ovarian failure or premature ovarian failure has most
recently been called primary ovarian insufficiency. Please
refer to the appropriate section on our website for a
complete discussion of this disorder.
Approximately 40% of the patients seen at the Texas Fertility Center
have ovulatory dysfunction. Fortunately, this is one of the most
easily treated conditions in our practice, and the overwhelming
majority of patients with this disorder eventually do successfully
conceive.
Luteal phase defect is a condition that is associated with recurrent
miscarriage and possibly with infertility as well. An ovulatory
cycle is divided into two phases. The part of the cycle prior to
ovulation is called the follicular phase. During this time, the
follicle (the fluid filled sac within the ovary that contains the
oocyte) develops in preparation for release of the oocyte. The
developing follicle produces a type of estrogen (“estradiol”), that
stimulates growth or thickening of the uterine lining (the “endometrium”).
This estrogen production is also responsible for increasing the
cervical mucous production and changing its characteristics to make
it more favorable for sperm penetration. When release of the egg
occurs (“ovulation”), the cells remaining in the follicle undergo
changes that allow them to produce another hormone called
progesterone. This process is called “luteinization”, and it is
triggered by the release of a hormone called luteinizing hormone, or
LH. Following this LH surge, the follicle changes names and it
becomes the “corpus luteum”. This event is the beginning of the
luteal phase, which makes up the second half of a woman’s cycle.
The progesterone made by the corpus luteum causes changes to occur
within the endometrium that make it more favorable for embryo
attachment (“implantation”).
If
progesterone production is weaker than normal, the endometrium may
not develop sufficiently for an embryo to implant. This situation is
called a luteal phase defect. The developing endometrium is
dependent on adequate progesterone production from the ovary.
Although many physicians focus on the blood progesterone level, it
is actually more important that progesterone production be of a
sufficient quantity for an appropriate number of days. The absolute
serum level of the hormone is not as important. Therefore, simply
measuring the serum level may be misleading. It is more accurate to
evaluate the effect of progesterone on the endometrium over time.
This is accomplished by examining a piece of uterine lining tissue
under a microscope, a procedure call an endometrial biopsy. This
biopsy is obtained close to the end of the luteal phase, which is
the most accurate time to evaluate the luteal phase. Another
acceptable (and far less uncomfortable) way of evaluating the luteal
phase is to count the number of days from the time of ovulation
until the woman begins her next menses. A normal luteal phase needs
to be at least 12 days.
The
most common treatment for a short luteal phase is to give the woman
extra progesterone. Progesterone supplementation can effectively
prevent the loss of a pregnancy when given to women with a luteal
phase defect. Usually, progesterone supplementation is begun three
days following ovulation. It is therefore important to accurately
document the day of ovulation, as starting progesterone too soon may
increase the risk of a tubal pregnancy. It is common for women to
use a urinary ovulation predictor kits to determine the day of
ovulation. As the LH surge typically precedes ovulation by 18-30
hours, progesterone supplementation is begun four days after the
initial detection of the LH surge.
Supplemental progesterone is given to all women undergoing in vitro
fertilization. In the past, intramuscular progesterone was utilized
exclusively for IVF supplementation. Recent data, including one of
the largest studies on this topic – performed at TFC – suggest that
other methods of progesterone supplementation, such as a vaginal
gel, are just as effective, if not more so. Oral progesterone is not
as effective because of its short half life, and also because it may
be broken down by stomach acid. When a medication has a short half
life, it needs to be given more frequently to maintain adequate
levels in the circulation.
Luteal phase defect is a significant cause of recurrent miscarriage
– and possible infertility as well – that, once diagnosed, is easily
treatable.
The
average age of menopause (or “ovarian failure”) in the United States
is approximately 51 years of age, however the average age of loss of
fertility in women appears to be around 45-47 years of age.
Premature ovarian failure (POF) is defined as the loss of ovarian
function before age 35. Ovarian failure results from the loss of
oocytes from the ovary, which leads to an inability of the ovary to
produce estrogen. Common symptoms include the cessation of menses,
and the development of hot flushes and vaginal dryness. Obviously,
complete ovarian failure results in permanent infertility.
POF
usually results from a genetically predetermined loss of a woman’s
oocytes. However, it can also be the consequence of the ovary having
been damaged or destroyed by disease processes. One of the most
common diseases is endometriosis. Also, benign ovarian tumors and
borderline malignant tumors of the ovary can destroy the ovary.
Surgical treatment of these diseases can result in the removal of
normal ovarian tissue as well. It is not uncommon for women to lose
an ovary from surgery for a fallopian tube problem and/or a surgery
for a benign ovarian problem. A much less common condition is
destruction of the ovary from an autoimmune process where a woman
develops anti-ovarian antibodies that attack the egg containing
follicles in the ovary.
All
women with POF should have a chromosomal evaluation, which can be
performed by a simple blood test. The majority of women with POF
will have a normal chromosomal evaluation. However, occasionally a
small fragment of the Y chromosome may be detected. In this
situation, the ovaries should be removed as soon as possible because
there is an increased chance of developing ovarian cancer. Usually
the removal of the ovaries can be achieved laparoscopically.
Although the diagnosis of POF is often devastating to a couple
attempting pregnancy, it is still possible for an affected woman to
achieve pregnancy through the use of donor oocytes (see the section
on donor oocyte cycles). If the woman has a younger sister, she may
be a candidate for donating oocytes. The advantage of utilizing the
woman’s sister’s oocytes is that this will enable the woman to pass
along her family’s genetic material to her children. It is
worthwhile to educate the woman’s younger sister about POF since the
cause is commonly genetic and she may eventually experience the same
problem. If the patient does not have a younger sister, or if her
sister is similarly affected with POF, another viable option for
pregnancy is the use of oocytes donated by an anonymous donor.
Regardless of the source of the donated eggs, the success of IVF
using donor oocytes is quite high.
Since women with POF have a significant deficiency in estrogen
production, they should consider taking estrogen replacement therapy
while they are evaluating their fertility options and as soon as
possible after they deliver a baby. Replacing estrogen usually
alleviates the symptoms of estrogen deficiency as well as other
associated conditions that can ultimately develop such as the
premature development of significant bone loss (osteoporosis). All
patients with POF should discuss estrogen replacement with their
primary care physician to see if they are good candidates for
estrogen replacement therapy.
