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Kirtly Parker Jones, M.D.
Associate Professor
Department of OB/GYN
U of U College of Medicine
"A chicken is only an egg's way of making another egg"
Samuel Butler
Adrenarche: the increase in secretion of androgens by the adrenal gland, occurring from about age 5 to age 20
Gonadarche: the initiation of production of significant amount of sex steroids by the testis or the ovary related to stimulation by gonadotropins
Puberty: the physical and biochemical changes associated with maturation of the hypothalamic/pituitary/gonadal axis which lead to the development of secondary sex characteristics and reproductive function - usually the co-ordinated consequences of adrenarche and gonadarche
Menopause: the final spontaneous menstrual period (occurring at about 50 years of age in American women)
Climacteric: the period of transition from predictable ovarian function through the postmenopausal years, a period marked by waning ovarian function and dramatic decline in estrogen production
Perimenopause: the period before and after the final menstrual period marked by fluctuating ovarian function - a period of about 4 years on average
Outline
Although puberty occurs when increased gonadotropin secretions by the pituitary
stimulate the gonads, the stage has been set during fetal life. In males, the earliest secretion of
testosterone at 7 to 8 weeks gestation occurs independent of gonadotropin and continues with
stimulation of hCG. The hypothalamic/pituitary axis completes development at about 20 weeks
gestation. Gonadotropins become sensitive to estrogen feedback suppression and fall to undetectable
levels.
Immediately after birth, the stimulatory effect of hCG on the male testis, and the
suppressive effect of placental estrogens and progesterone on the pituitary and hypothalamus are
withdrawn, leading to a rapid rise in gonadotropins. The withdrawal of placental hormones may actually
lead to scant vaginal bleeding in females as well as temporary nipple discharge. The subsequent pattern
of gonadotropin hormone levels and gonadal response differs in infant boys and girls. In girls, there is a
fall in estradiol levels in the first week of life, and then a gradual minimal rise that continues for one to
two years. In boys, testosterone levels rapidly decrease in the first week of life, and then increase to
pubertal levels for two to four months before declining.
The period between infancy and puberty are marked by very low levels of
gonadotropins and gonadal steroids. Even in children without functioning gonads (Turner's Syndrome,
XO gonadal dysgenesis), the gonadotropins remain low suggesting a profound suppression of the
hypothalamic GnRH center. Classic experiments in the rhesus monkey by Knobil (for which the Nobel
Prize in medicine was awarded) reveal that the administration of pulsatile GnRH to the prepubertal
monkey can initiate puberty.
The finding that the administration of pulsatile GnRH can initiate puberty and
experimentally induced lesions in the anterior hypothalamus in animals can cause precocious puberty
suggest that there is an active "off" center which suppresses the pulsatile release of GnRH. Accidents in
nature in humans (hypothalamic tumors, hydrocephalus, epilepsy) can lead to precocious puberty in
boys and girls. To date, no specific locus of suppression which is destroyed by tumors or turned "off" at
puberty has been found in humans.
Human puberty is defined as the transition between the juvenile state and the mature
reproductive state when secondary sex characteristics develop and fertility is achieved. It is composed
of the relatively synchronous processes of adrenarche and gonadarche. Adrenarche occurs usually one
to two years before gonadarche and is independent of gonadarche. Children without functioning gonads
will achieve adrenarche. Puberty includes the adolescent growth spurt, growth of pubic and axillary hair
in males and females, and specific secondary sex characteristics for males and females.
The age of puberty has been decreasing over the past several hundred years of written
documentation in Europe and the United States. Although the age of male puberty is not as well
documented as females, suggestions from northern European village records suggest that the age of
menarche may have declined from as late as 18 to the current 12.8 years. There are clear differences in
racial norms of puberty with African-Americans and Latinos achieving puberty at a slightly earlier age
on average than European- Americans.
The earliest manifestation of puberty in females is adrenarche. The rise in serum DHEA
and DHEAS may have no clinical signs or symptoms, therefore, the first sign of puberty in females is
usually defined as the initiation of breast buds. The breast develops under unopposed low dose
estrogen stimulation for about 2 years before the first menses. During this time, pubic and axillary hair
become evident and there is a growth spurt. Weight gain occurs with increase in height, but also, there
is an increase in body fat as distributed in the breasts, mons pubis, hips and thighs. The vagina lengthens
and becomes rugated and the labia majora and minora become thickened and rugated.
The first menses occurs about 2 years after breast bud development, and is usually the
result of fluctuating estrogens associated with follicle development without ovulation. Ovulation usually
occurs within 6 months from the first episode of vaginal bleeding. The breast and pubic hair
development as well as vertical growth and fat deposition continues for several years after the first
menses.
As in females, puberty begins with adrenarche which also has limited clinical
manifestations in boys. The first clinical manifestation is testicular enlargement which begins at a mean
age of 11.6, which is followed in the next 2 years by pubic hair. Adult size and shape of the penis and
scrotum is achieved between ages 12 and 17 with an average of about 15 years of age and pubic hair
completes development at about the same time.
The testosterone effect on the vocal cords leads to the beginnings of voice changing at
an average age of 13, accompanied by the onset of spermatogenesis. The growth spurt continues with
45% of the adult skeletal mass acquired between age 11 and age 18. Prior to puberty, male and
females have similar muscle mass, but by the end of puberty, the average male has 56% more muscle
mass than the average female.
The emotional responses to the changes in gonadal steroid are poorly understood,
although all families and societies describe a marked change in pubertal children with respect to their
relationships with their parents, their peers and members of the opposite gender. Violent events by
males increase dramatically in adolescence, but whether this is a direct effect of gonadal steroids on
behavior or a function of the individual adolescent's character and societal roles is not clear.
Delayed puberty may be due to dysfunction of the hypothalamic/pituitary axis, end
organ failure, or idiopathic. Constitutional delay of puberty may be due to chronic severe medical illness,
weight loss or malnourishment,or physical stress(including chronic strenuous exercise). Adrenarche
usually occurs but gonadarche does not follow. Delayed puberty may also be due to pituitary or
hypothalamic tumors, pituitary failure, or congenital absence of GnRH neurons.
Gonadal failure in boys or girls may be due to chromosomal anomalies (Turner's syndrome),
exposure to high dose chemotherapy or radiation to the pelvis in childhood, autoimmune, or idiopathic.
Adrenarche also still occurs (except in those children with pituitary and subsequent adrenal failure), but
development of secondary sex characteristics does not follow. An evaluation of delayed puberty should
be evaluated in girls who have no evidence of breast development by age 14, and in boys who have no
evidence of genital growth by age 15.
The reliability of ovarian function, both hormonally and reproductively peaks in the mid
to late 20's. Beginning in the early thirties, there is epidemiologic evidence of a decline in fertility. By
the mid thirties, there are subtle changes in the levels of FSH in the early follicular phase which become
more marked in the 40's. These changes may not be reflected in clearly noticeable changes in the
experience of an individual woman's menstrual cycle. As the mid 40s arrive, there may be a shortening
of the length of the menstrual cycle which is a reflection of a declining pool of oocytes, declining inhibin,
rising FSH and earlier efforts at recruitment and ovulation of the dominant follicle. The nature of these
changes as perceived by an individual woman will be very different from person to person.
The perimenopause is defined as that period around the menopause which is marked by
unpredictable ovarian function and menstrual irregularity. Epidemiologic studies of normal women
suggest that this is a period of about 4 years around the menopause although the variation from woman
to woman is large. This time is marked by unpredictable ovulation and periods of both higher and lower
that usual estrogen levels. Uterine bleeding may be more or less than "usual" in flow and the timing of
uterine bleeding is also unpredictable.
There are numerous physical and psychological phenomena attributed to this time of
reproductive life (mood swings, vasomotor flushes, sleep disturbances, headaches, memory problems,
decreased libido, urinary incontinence) but it is not clear which are related to fluctuations of ovarian
function, which are related to aging, and which are psycho-social responses to mid-life which may vary
from person to person and culture to culture.
The menopause is the retrospective diagnosis of the "final" spontaneous menstrual
period. Usually a woman in her 50's who has not had a period for over a year may look back and note
that her "menopause" was on a specific date of her last spontaneous period. The average age of
menopause in American women is 51. Various inherited and environmental factors influence the age of
menopause. Cigarette smoking, living at high altitude, exposure to some chemotherapeutic agents, and
hysterectomy tend to slightly lower the age of menopause or final cessation of ovulation.
The climacteric is a term used for the transitional period including the perimenopause
and the several years after the menopause. There are specific symptoms which some women may
experience which are directly attributable to estrogen withdrawal (vasomotor flushes, urogenital
atrophy) and there are some long term aging and disease processes which are worsened by estrogen
withdrawal (osteoporosis, coronary artery disease). There are number of other symptoms of aging
which may be worsened by estrogen withdrawal (arthritis symptoms, cognitive function) but the
evidence is not so clear.
The post-menopausal ovary is still capable of producing substantial amount of weak androgens
(ovarian stroma stimulated by menopausal levels of LH) which are peripherally converted to estrogens.
The eventual cessation of ovulation is a "normal" event in human development. Until the last
several hundred years, human life span was usually less than 50 years of age. The existence of a
population of women who predictably lived well beyond the age of reproduction is new in human
history. Through epidemiologic studies in aging women, many who took estrogen hormones for the
treatment of vasomotor flushes, it was noted that long term estrogen users had decreased incidence of
complications of osteoporosis and coronary artery disease. The health benefits and risks of estrogen
therapy after menopause have been continuously evaluated over the past 35 years and this therapy is
now being subjected to prospective randomized trials.
Observations from women who had a uterus and took only estrogen after menopause revealed
an increased risk of uterine cancer. Unopposed estrogen stimulation of the uterus, whether due to
endogenous estrogens or estrogen therapy, causes endometrial hyperplasia and potentially
adenocarcinoma of the uterus. The intermittent addition of progestational agents for 12 days each
month causing endometrial shedding eliminates this increased risk. For older women, the thought of
monthly periods is unattractive and is one of the major reasons for lack of compliance in post-
menopausal hormone therapy. Another concern is the possibility of a small increase in the risk of breast
cancer in long term estrogen users. Exogenous estrogens for the menopause may also have a very small
increased risk of deep venous thrombosis and gall stone formation. Formulations for estrogens and
progestins and combinations of both will be changing dramatically in the years to come as clinical
research develops methods and formulations which protect the heart and bone but do not stimulate the
endometrium or breast.
The search for a physiologic event in men which would correlate to the menopause in women
has been largely unsuccessful. The "male menopause" as a definable gonadal event does not exist.
Although the secretion of testosterone gradually decline with advanced age, the rate after 40 is about
1% per year and is not enough to account for any decrease in libido or erectile function. Rather, the
problems associated with loss of desire or erectile dysfunction are related to disease states or specific
changes related to aging and not testosterone levels, themselves. The concept of a gradual decline in
adrenal androgenic steroids (DHEA and DHEAS) which begins in the mid to late 20's and may lead to
some decrease in physical vigor and musculoskeletal flexibility has recently received a great deal of
press coverage and these hormones are readily available at most supermarkets and health food stores
without a prescription. As DHEAS levels in men decrease by 50% from 20 years of age to 50 years of
age, there is a great deal of interest in these hormones as a potential "fountain of youth" for men.
Limited prospective randomized studies suggest that the administration of DHEAS in middle aged men
does increase lean body mass.
With an aging population and the specter of a generation of physically incapacitated elderly men
and women, te search for anabolic agents which will maintain musculoskeletal strength has become
more intense. Several studies on the administration of Growth Hormone in elderly men suggest that it
may increase lean body mass and strength in older men.
In numerous cross cultural studies of men and women, there does not appear to be a well
defined entity called the "mid-life crisis". In both men and women, there is no well defined increase in
major depression or major affective disorders in mid-life. Women at the time of menopause do have
more concerns about health and aging than do men of similar age. However, the concepts of
"involutional melancholia", "empty nest syndrome", "mid-life crisis" do not exist as normative events in
the life cycle of men and women.
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Endocrinology (Third Ed), Yen and Jaffe eds, W B Saunders, Philadelphia, 1991
Grumbach MM, Sizonenko PC, Aubert ML eds. Control of the Onset of Puberty. Williams
and Wilkins, Baltimore, 1990
Mishell DR. Menopause: Physiology and Pharmacology. Year Book Medical Publishers,
Chicago, 1987
Yanovski JA, Cutler GB. "The Reproductive Axis: Pubertal Activation" in Reproductive
Endocrinology, Surgery, and Technology, Adashi, Rock, Rosenwaks eds. Lippincott-Ravin,
Philadelphia, 1996