Female Reproductive Life
7 year old girl with a history of rapid growth in height over the past 1-2 years (now clearly the tallest
person in her first grade class), development of breast buds and mounds over the past 6-12 months, growth of pubic
and axillary (arm pit) hair over the past 6 months, and now the recent onset of vaginal bleeding.
Is a medical evaluation for this girl important?
The timing of puberty (in industrialized societies) has been fairly well characterized. The normal range (time limits)
for pubertal changes is most often considered to be the mean time of occurrence +/- (plus or minus) 2.5 standard
deviations from the mean. If this definition is accepted, then pubertal changes prior to the age of 8 year old are
Early (precocious) puberty generally deserves a clinical evaluation. Early puberty occurs in girls roughly 5 times more
often than in boys. Most often (about 75% of the time) the cause of the precocious puberty remains unknown even following
a thorough clinical evaluation. In girls undergoing pubertal changes prior to the age of 4 the cause is often a brain lesion.
In girls who have pubertal changes after the age of 4 the cause is usually not found.
In a situation like this one, the clinical evaluation may initially include (a) a thorough history (the timing of the
pubertal changes that have occurred, height and weight percentile records, any medication or drug ingestion, any prior
trauma to the head, and other (social, cognitive or emotional) developmental changes), (b) radiologic tests for bone age
(left wrist xray films are often obtained and atlases can then be used to determine the bone age), (c) CT or MRI of the
head and brain to rule out (potentially life threatening) tumors or lesions, (d) bloodwork for a hormone evaluation
(including gonadotropin levels, hCG, DHEAS, testosterone, estradiol, and TSH), (e) an ultrasound of the pelvis (to exclude
an ovarian tumor), and (f) a physical exam (confirm pubertal changes in breasts and pubic hair, examine vaginal vault as
best able to rule out the presence of a foreign body as the cause of bleeding, height-- which can be used with charts along
with the bone age to predict the ultimate height of the child if untreated, and evidence of androgen excess with male
pattern hair growth or virilization).
In girls with precocious puberty, about 75% of the time a cause is not identified. About 10% of the time (female precocious
puberty) an ovarian tumor or cyst is found, with almost all of these being estrogen producing "granulosa cell" tumors
(although non estrogen producing tumors can also cause early pubertal changes). About 5-10% of the time (female precocious
puberty), a head or brain problem is found which may include a variety of lesions (such as abnormal bony skull development,
hypothalamic hamartomas that are composed of an abnormal mix of tissues, tumors such as a craniopharyngioma, recent trauma
to the skull or brain, infection like encephalitis or meningitis, and hydrocephalus). About 3-5% of the time (female
precocious puberty), a disorder called McCune-Albright syndrome is identifiable (including multiple cystic bone lesions,
fragile bones that fracture easily, and various size and shape cafe au lait skin spots). Less than 1% of the time (female
precocious puberty), adrenal tumors or ectopic production of gonadotropins (by organs other than the pituitary gland) may
result in precocious puberty.
7 year old girl with a history of rapid growth in height over the past 1-2 years (now clearly the tallest
person in her first grade class), development of breast buds and mounds over the past 6-12 months, growth
of pubic and axillary (arm pit) hair over the past 6 months, and now the recent onset of vaginal bleeding.
Full clinical evaluation for a specific cause of early puberty is negative and the "diagnosis of exclusion"
(constitutional precocious puberty) is determined.
Is treatment important for this girl?
There may be a family tendency towards constitutional precocious puberty (premature maturation of the reproductive
hormone axis), which often occurs close to 8 years of age. Precocious puberty is not associated with premature menopause.
The two most important problems associated with constitutional precocious puberty are short stature (become short adults)
and various forms of (predominantly sexual) abuse.
In the early 1950s standard tables (such as the Bayley-Pinneau Tables) became available that correlate the
"present skeletal age" (determined by x-ray exam of bones such as those within the wrist) and "current height" to
determine the "ultimate predicted height." If the ultimate predicted height is less than (say) 5 feet tall, then
treatment of the precocious puberty to reduce the estrogen effect on the bones appears to be reasonable.
The girl's cognitive, emotional and social development is determined predominantly by her chronologic age and the type
of and level of her experiences rather than by the development of her secondary sexual characteristics. Her classmates,
friends and even adults can misunderstand this. This misunderstanding can result in serious difficulties in social and
emotional development and may even result in various forms of sexual abuse.
For these reasons, a girl with precocious puberty involving an increase in skeletal height, breast formation, pubic hair
growth and menses deserves treatment whenever possible.
5 year old girl with the recent onset of vaginal bleeding. There is no history of a growth spurt
(rapid increase in height), no (development of) breast buds, and no growth of pubic or axillary (arm pit) hair.
Is evaluation and treatment for this girl important?
Isolated premature vaginal bleeding is a rare presentation for (true) precocious puberty. Most often the vaginal
bleeding is due to another cause.
The presence of a foreign body within the vagina is not uncommon for girls with this history. Girls may place crayons
or the like into the vaginal vault and this may result in bleeding. A careful exam of the vicinity and the vaginal vault
(as best possible or when appropriate) is suggested.
Local trauma may cause bleeding predominantly from the outside of the vaginal orifice or adjacent thigh. Straddle injuries
in which the inner thigh(s) or external genitalia are traumatized and bleeding may occur as a girl is climbing over a
fence and falls, while jumping from (or falling from) a bicycle seat onto the railing of the bike especially when the
bicycle is too big for the girl, etc.
Sexual abuse should (always) be considered and excluded. Local infections and tumors should also be considered.
15 year old girl has not yet entered puberty. The girl has some pubic hair growth but virtually no breast budding and has not yet menstruated. The girl's family is concerned that "something is wrong."
What evaluation of this girl is appropriate?
The U.S. Health Examination Survey that was published in 1980 described the secondary sexual characteristics in girls ranging from 12 to 17 years of age. Virtually all US white girls and all US black girls reportedly entered puberty by age 13.
Physiological delayed puberty (otherwise normal late bloomer) tends to run in families and is generally uncommon. A directed clinical evaluation should be seriously considered whenever menarche (the onset of menses) has not occurred in (a) a 14 year old girl who also has not initiated the growth spurt or developed any secondary sexual characteristics, (b) a 16 year old girl regardless of the growth spurt or any secondary sexual characteristics, and (c) a girl of any age in which the family is very concerned that something is wrong.
Statistically, the most common cause for delayed puberty is ovarian failure. Premature ovarian failure (menopause) may occur in as many as 40-45% of those with delayed puberty and is demonstrated by gonadotropin (FSH and LH) concentrations (in the blood) within the menopausal range with a (concurrent) suppressed estradiol concentration. A chromosome analysis is very important in young girls with premature ovarian failure.
If the gonadotropin concentrations are normal, then anatomic (structural) defects need to be considered. Mullerian agenesis (absence of the Mullerian ducts that ultimately normally form the fallopian tubes and uterus) typically results in an absent or small vaginal vault and no uterus or fallopian tubes. Mullerian agenesis occurs in roughly 1 in 4000 female births and is the second most common cause of primary amenorrhea (significant delay in the onset of menses) behind premature ovarian failure. Other structural defects that may result in delayed menses include a vaginal septum (tissue within the vaginal vault that runs transversely to block to outflow of menstrual flow) or an imperforate hymen (tissue at the opening of the vaginal canal that can block the flow of menstrual blood). Both the vaginal septum and imperforate hymen result in a "backup" of menstrual flow to generally cause significant pelvic pain.
If the gonadotropin concentrations are low, then a wide variety of conditions should be considered. Possibly 10% of delayed puberty is simply due to a physiologic delay in the maturation of the reproductive axis (the "late bloomers"). Physical stress (as with anorexia, elite athletes, medical illness) or severe emotional stress can cause delayed menses. Hormone abnormalities (prolactin, thyroid, pituitary, adrenal), brain tumors (such as craniopharyngiomas or pituitary adenomas) and some illicit drugs (such as opiates and marijuana) should also be excluded.
The initial clinical evaluation should include (a) a thorough history (including height and weight percentile recordings, presence of hot flashes, significant emotional stress, eating and exercise habits, illicit drug use), (b) radiologic assessment of bone age (left wrist films are generally used, with a delay in bone age in those with a physiologic delay in puberty), (c) bloodwork for hormone evaluation (gonadotropins, estradiol, hCG, TSH, prolactin, adrenal steroids if symptomatic) and chromosomes if the gonadotropins are elevated, (d) CT or MRI of the skull and brain (to assess tumors or lesions), and (e) a physical exam (to rule out a structural obstruction or absence of the uterus). A progesterone challenge test can determine whether there is appropriate estrogen stimulation of endometrial (uterine lining) growth and a normal outflow tract (ability to release the endometrial tissue that is shed during menses through the cervix and vagina).
22 year old G0 with a history of irregular menstrual intervals every 3-6 months and a diagnostic evaluation suggesting anovulation (absence of ovulation). Patient attempts ovulation induction with (injectable FSH containing) fertility medications. Ultrasound monitoring of follicle development during ovulation induction determines that only 15-20 follicles begin to grow (mature) during any given cycle of controlled ovarian hyperstimulation.
If about 1000 eggs are used (become degenerate) each month (a normal menstrual cycle interval) then why do only 15-20 begin to grow when induced with (FSH containing) fertility medications?
A woman will typically deplete her ovarian reserve (number of eggs within the ovaries that are able to mature) by about 1000 eggs per month during the reproductive years.
During the course of this reproductive lifespan there may be (short) periods of accelerated loss but these do not fully account for the tremendous number of eggs (300 to 400 thousand) that become degenerate over the entire 30-40 year reproductive life.
It appears that the majority of these 1000 eggs per cycle degenerate (or become atretic) prior to the onset of the cycle.
When a young woman with an abundant ovarian reserve undergoes controlled ovarian hyperstimulation with FSH containing fertility medication usually only 10-25 eggs begin to develop. The number of "recruitable" follicles with these medications is roughly proportional to the woman's ovarian reserve, which is also related to her age. In a woman with a depleted ovarian reserve often only 1 to 3 eggs mature per cycle of controlled ovarian stimulation.
The molecular events that orchestrate which ovarian follicles develop the ability to respond to FSH and which follicles (committed for that particular cycle) become degenerate (atretic) are largely unknown. Most research in this area is based on either (a) the structural appearance (morphology) of follicles within human ovarian tissue biopsies or (b) primate animal research examining egg development in lower animals.
Basically, research suggests that human follicles develop the ability to respond to stimulation (by FSH = Follicle Stimulating Hormone) over a several (3-6) month period of time during which they change significantly and acquire functional FSH receptors. At the onset (or a few days prior to the onset) of a menstrual cycle there are several follicles (up to 20 or 30) specifically prepared by the ovary "for that cycle of development." The remaining 970 to 980 follicles "for that cycle of development" have (seemingly) already become degenerate or atretic (incapable of maturation).
31 year old G1 P1 now with an 8 month history of amenorrhea (absence of menses) and the recent onset of hot flashes with insomnia. Laboratory evaluation is consistent with menopause (elevated FSH and suppressed estradiol concentrations).
Is it possible to have menopause at 31 years of age? Is there any chance of future childbearing for this woman?
Yes (to both questions).
The average age of menopause in the USA is 51-52 years old. Premature ovarian failure (POF) is the occurrence of ovarian failure at less than 40 years of age (with an incidence rate of about 1%). The two most common causes of premature ovarian failure seem to be (a) a genetic defect in (one of) the X chromosomes that accelerates the rate of depletion of eggs within the ovaries (the "normal" genes may allow for an extended reproductive lifespan of 30-40 years while if abnormal then there is a shorter reproductive lifespan), and (b) an autoimmune disorder in which the woman's immune system appears to "attack" the ovary and prevents the eggs from developing.
There is a (small) chance (less than 5%) that the woman's ovaries will spontaneously "escape" suppression if the cause is autoimmune, resulting in (typically short) periods of time during which ovulation and pregnancy may occur.
Many medical treatments have attempted to increase the likelihood of ovulation in women with POF but none have been shown to be reliable (clinically useful). I suggest hormone replacement therapy for premature ovarian failure patients under my care, which contains noncontraceptive doses of estrogen and progesterone. If the woman begins to have breakthrough bleeding during these hormone replacement cycles then spontaneous ovulation may be occurring. During the time periods when spontaneous ovulation occurs, I discontinue the hormone replacement medication and suggest attempting pregnancy (if desired).
38 year old G0 with (late) menarche (onset of menses) at age 18 and a lifelong history of anovulation (absence of ovulation) secondary to birth control pills now desires fertility.
Does the timing (early or late) of menarche or (long time) occurrence of anovulation suggest that this 38 year old woman might have a greater ovarian reserve than the average 38 year old?
A woman "uses up" eggs constantly (until menopause) regardless of whether any of the eggs fully mature (ovulate). A female fetus at 20 weeks gestation (half way through pregnancy within her mother's uterus) has the most eggs that she will ever have (about 7-8 million eggs), at birth she only has 1-2 million eggs (the most rapid period of loss of her eggs occurs prior to being born), and at puberty she only has 300-400 thousand eggs (less than half of the amount she was born with). Throughout the reproductive years, eggs become degenerate regardless of whether any are matured fully and ovulate.
The rate at which eggs are "used up" seems to vary from woman to woman. Every 40 year old has less eggs than she had when she was 30 years of age, but some 40 year olds have more eggs left than (say) an average 33 year old (since they apparently use up their eggs relatively slowly). Tests to assess the ovarian reserve have been developed to help determine the number of maturation capable eggs remaining in a particular woman's ovaries.
The age of menarche and long periods of anovulation do not appear to relate in any predictable way to a woman's ovarian reserve. Of note is that cigarette smoking is one of the only factors known to accelerate the depletion of eggs within a woman's ovaries (associated with menopause 1-2 years earlier than otherwise predicted).
42 year old G2 P2 desiring fertility has an assessment of ovarian reserve using the cycle day 3 bloodwork and the clomiphene challenge test. The results are encouraging.
Does age relate to fertility independently of the assessment of ovarian reserve as determined by these hormone tests?
The hormonal assessment of ovarian reserve has predominantly been correlated with the woman's response to (FSH containing) fertility medications and subsequent success at In Vitro Fertilization (or other ARTs). The number of recruitable follicles at the onset of a menstrual cycle (or cycle of controlled ovarian hyperstimulation) is thought to be proportional to the number of (maturation capable) eggs remaining in the ovaries.
The "reproductive potential" of a woman appears to relate to both her chronological age and the assessment of her ovarian reserve. In women with uniformly encouraging ovarian reserves (as assessed by the hormone concentrations) the (pregnancy) success at In Vitro Fertilization (or other ARTs) is still strongly associated with the woman's age, with a predictable decline in pregnancy rates (and increase in spontaneous pregnancy loss rates) with advancing maternal age.
25 year old G0 with history of bilateral (right and left side) ovarian cystectomies for endometriosis (endometriomas), now with a relatively discouraging assessment of ovarian reserve.
Does this woman's relative youth suggest that she has an improved (pregnancy) success rate compared to older women with the same ovarian reserve assessment results?
There are few good quality research articles in the literature that provide data that can be used to answer this question. The available data suggests that women with a discouraging ovarian reserve (by hormone assessment) do not do well (in terms of pregnancy) when they undergo controlled ovarian hyperstimulation (using FSH containing medications) either with intrauterine inseminations or In Vitro Fertilization.
The "assessment of a woman's ovarian reserve" and/or the "woman's age" may each independently discourage one from recommending the use of FSH containing medications during a review of treatment options. However, if the assessment of ovarian reserve is borderline (rather than clearly discouraging) then the woman's age (youth) may reasonably allow one to be more encouraging.
It should be remembered that the assessment of a woman's ovarian reserve has not (to my knowledge) been studied with respect to her reproductive potential in any context except for those in which fertility medications are used.
It may be possible (and indeed has been my own anecdotal clinical experience) that women with decreased ovarian reserves (by hormone testing alone) or decreased reproductive potential (by chronological age) often become pregnant in spontaneous (natural) cycles. For these women, treatment options directed at improving the function of the pelvis (intrauterine inseminations if there is an abnormal postcoital test result, or operative laparoscopy and operative hysteroscopy if there is a suspected anatomic abnormality) should be considered and may be of tremendous value.