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The Beginning and End of Reproductive Life: Pubertal and Midlife Changes

Kirtly Parker Jones, M.D.
Associate Professor
Department of OB/GYN
U of U College of Medicine

Definitions

Outline

Take Home Points





"A chicken is only an egg's way of making another egg"

Samuel Butler






Definitions

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

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Outline

  1. Ontogeny of the Reproductive system in Humans

  2. Normal Puberty

  3. The End of Reproductive Life in Women

  4. Male Climacteric-Does it Exist?

  5. Bibliography

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Outline

  1. Ontogeny of the Reproductive system in Humans

    1. Fetal Life

      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.

    2. Neonatal Life

      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male testis, and the suppressive effect of placental estrogens and progesterone on the pituitary and hypothalamus are withdrawn, leading to a rapid rise in gonadotropins.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.

    3. Childhood

      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.

    4. Errors in Suppression-Precocious 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.

  2. Normal Puberty

    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.

    1. Females

      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.

    2. Males

      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.

    3. Errors in Puberty-Delayed Puberty

      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.



  3. The End of Reproductive Life in Women

    1. Perimenopause

      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.

    2. Menopause

      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.

    3. Climacteric

      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.

    4. Issues in Hormone "Replacement"

      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.



  4. Male Climacteric-Does it Exist?

    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.

  5. Bibliography

    Grumbach MM, Styne AM. "Disorders of Puberty in the Male and Female" in Reproductive 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

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Take Home Points

  1. Puberty is the coordinated sequence of biochemical and physiologic events including adrenarche and gonadarche which result in the growth spurt of adolescence, development of secondary sex characteristics, and reproductive capacity.

  2. The CNS activation of puberty may occur prematurely (before the age of 8 in girls or 9 in boys) or be delayed (age 14 in girls and 15 in boys), often indicating underlying medical disease.

  3. The cessation of predictable ovarian function occurs over several years. The menopause is defined as the last spontaneous menstrual period.

  4. Estrogen therapy may substantially decrease the risk of postmenopausal osteoporotic fractures and has been shown in epidemiologic studies to decrease the risk of coronary artery disease.

  5. There is no clear rapid decline in gonadal function in men as there is in women, although there is a dramatic decline in adrenal androgens from their peak after puberty to middle age. Whether this is reflected in decreased function is unclear.

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