Physiology Puberty & Aging Lecture Notes 2024-25 PDF

Physiology: Puberty & Aging Reproductive System Page 1 of 13 Dr. Jeyasuria Pancharatnam Learning Objectives 1. To learn the definition of puberty and its stages 2. To understand the physiology of puberty 2.1 Steroidogenesis 2.2 Gonadotropins...

Physiology: Puberty & Aging Reproductive System Page 1 of 13 Dr. Jeyasuria Pancharatnam Learning Objectives 1. To learn the definition of puberty and its stages 2. To understand the physiology of puberty 2.1 Steroidogenesis 2.2 Gonadotropins 2.3 The control of the onset of puberty 2.4 Gonadal Steroids 3. To recognize the signs and symptoms of precocious puberty and delayed puberty 4. Define the aging outcome in reproductive systems in men and women- Menopause and Andropause 5. 1. To learn the definition of puberty and its stages Puberty is the period during which adolescents reach sexual maturity and become capable of reproduction. Puberty occurs in boys between 9 and 14 years, and in girls between 8 and 13 years of age. Puberty is driven by two physiological processes: adrenarche and gonadarche. Adrenarche precedes gonadarche and is comprised of maturation of the adrenal cortex associated with increased secretion of adrenal androgens: dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione. Adrenarche leads to the appearance of sexual hair (pubarche). Gonadarche is comprised of growth and maturation of the gonads and is associated with increased secretion of sex steroids. Gonadarche is characterized by the initiation of folliculogenesis and ovulation in the female and spermatogenesis in the male. Gonadarche leads to thelarche (Breast Development) and menarche in girls and testicular enlargement in boys. 2. Define Menopause and Andropause Menopause- Cause and Effect- Changes in hormone and steroid feedbacks that result in menopause. Andropause- Explain how aging and the decline of androgen production leads to andropause. Physiology: Puberty & Aging Reproductive System Page 2 of 13 Dr. Jeyasuria Pancharatnam For both sexes, the genital and pubic hair changes that unfold at puberty are classified into five stages: stage 1 is prepubertal and stage 5 is adult (Figure 1, 1B and associated tables). The onset of adrenarche and gonadarche is related to Tanner Stage 2. Figure 1. Tanner stages in girls vary from child to child, but rather is related to the level of sexual maturation. There are several factors that influence the onset of normal puberty including racial and ethnic influences, socioeconomic conditions (developed vs. undeveloped countries), nutrition and disease (e.g. obesity and BMI), stress and psychosocial factors. Physiology: Puberty & Aging Reproductive System Page 3 of 13 Dr. Jeyasuria Pancharatnam Figure 1B: Tanner stages in boys Male Development: The enlargement of the penis and the changes in the secondary characteristics of the male are androgen dependent. One of the outcomes of puberty in the male is that the testes increase testosterone in the circulation and together with DHT production through 5 α reductase enzyme there are changes in male specific secondary characteristics. The vocal cord increase in length by 50% and the voice deepens when compared to girls at this stage. Muscles develop in strength and size through androgens anabolic effects. Body hair is also differentially developed in males where there is an increase in hair on the body surface as well as the growth of facial hair (beards and mustaches). Figure References 1) Marshall WA, Tanner JM: Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13, 1970. 2) Tables are from the online text “Endocrine and Reproductive Physiology, Fifth Edition” by White, Bruce A., PhD; Harrison, John R., PhD; Mehlmann, Lisa M., PhD; 2019, Elsevier Inc. Physiology: Puberty & Aging Reproductive System Page 4 of 13 Dr. Jeyasuria Pancharatnam To understand the physiology of puberty 2.1 Steroidogenesis: Synthesis of steroids from cholesterol that requires expression of specific enzymes and other proteins in the adrenal cortex and the gonads. The biosynthetic pathways for gonadal and adrenal steroids are important in understanding the physiology and pathophysiology of puberty. Figure 2 shows pathways of adrenal, ovarian, and testicular steroidogenesis. Genes responsible Figure 2. Steroidogenesis for specific enzymatic steps are indicated as well. Steroidogenesis in the zona fasciculate of the adrenal cortex is primarily governed by adrenocorticotropin (ACTH). Increased gonadal steroidogenesis and the completion of gametogenesis during gonadarche are stimulated by enhanced secretion of the gonadotropins, LH and FSH. 2.2 Gonadotropins The gonadotropin-releasing hormone (GnRH) is secreted by the GnRH-expressing neurons in the hypothalamus. Kisspeptin (KISS1)-expressing neurons in the medial basal hypothalamus synapse with GnRH neurons. Activation of the kisspeptin receptor (formerly called GPR54) on the GnRH neuron entrains the release of GnRH into the portal circulation, which induces the gonadotropes to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (Figure 3) GnRH secretion is pulsatile, and its release is influenced by testosterone and estrogen via a negative feedback effect. Figure 3. GnRH-expressing neurons Physiology: Puberty & Aging Reproductive System Page 5 of 13 Dr. Jeyasuria Pancharatnam Figure 4 illustrates the patterns of pulsatile GnRH release during development in boys and girls. Inset images indicate the frequency of pulsatile GnRH release at different stages of development. The frequency of GnRH pulses Figure 4. GnRH secretion patterns results in different effects: low- frequency pulses lead to FSH release Pulsatile GnRH release while high-frequency pulses will stimulate LH release. In girls, the frequency of the pulses varies during each menstrual cycle with a surge just before ovulation whereas, in males, the frequency is constant. Fetus Infantile Juvenile Pubertal Developmental stage This pulsatile pattern will occur Figure 5. GnRH in females throughout the day after maturation, and it will continue throughout the reproductive life of women into menopause (Figure 5). During the first 2 years after birth, plasma levels of LH and FSH rise intermittently to adult values and occasionally higher but then remain low until puberty. Physiology: Puberty & Aging Reproductive System Page 6 of 13 Dr. Jeyasuria Pancharatnam In girls, FSH levels rise during the early stages of puberty, and LH levels tend to rise in the later stages; from beginning to late puberty, the LH concentration rises more than 100-fold (Figure 6). In boys, FSH levels rise progressively through puberty, and LH levels rise and reach an early plateau (Figure 7). Figure 6. FSH and LH in girls Figure 7. FSH and LH in boys 2.3 The control of the onset of puberty Central dogma: The central nervous system (CNS) exercises the only major restraint on the onset of puberty. The neuroendocrine control of puberty is mediated by the hypothalamic GnRH-secreting neurosecretory neurons in the medial basal hypothalamus, which act as an endogenous pulse generator (oscillator). Physiology: Puberty & Aging Reproductive System Page 7 of 13 Dr. Jeyasuria Pancharatnam 2.4 Gonadal Steroids Testosterone Testosterone is secreted by the interstitial cells of the testes, and the Leydig cells (for more information about the physiology of testosterone, please see the “Male Reproductive Physiology Lecture”). Testosterone is involved in the maturation of the male reproductive organs, including spermatogenesis, and in the development of secondary sexual characteristics (body hair, increased muscle and bone mass, and the deepening of the voice). Testosterone is secreted during fetal life by the male testes and is responsible for the formation of external male genitalia and also the prostate gland, seminal vesicles, and male genital ducts. The levels of testosterone increase during puberty (Figure 7) to induce the appearance of secondary sexual characteristics in males and to support normal sperm development. Testosterone is directly correlated with stages of puberty and the aging of the bones (Figure 7). In pre-pubertal boys entering puberty, the secretion of LH and testosterone is related to the REM (rapid-eye movement) stage of sleep. Therefore, sleep is very important in the development of secondary sexual characteristics in young males undergoing puberty. With maturation, these hormones are subsequently secreted throughout the day. Estrogen Estrogen is a steroid hormone synthesized primarily by the ovaries and the placenta during pregnancy (for more information about the physiology of estrogen, please see the “Female Reproductive Physiology Lecture”). There are three forms of estrogen in women: estrone (E1), estradiol (E2), and estriol (E3). Estradiol is the main estrogen present during the reproductive period, while estriol is predominant during pregnancy and estrone during menopause. The main roles of estrogen are to promote the formation of female secondary sexual characteristics and to regulate the menstrual cycle. Estrogen is involved in promoting bone formation and also epiphyseal closure (it causes the long bones to stop growing). Similar to testosterone, plasma estradiol levels are correlated with the stage of puberty and bone age in girls (Figure 6). Physiology: Puberty & Aging Reproductive System Page 8 of 13 Dr. Jeyasuria Pancharatnam To recognize the signs and symptoms of precocious puberty and delayed puberty Precocious puberty represents precocious gonadarche and is the appearance of any sign of secondary sexual maturation before the lower limit of the normal age at onset of puberty (i.e., 9 years for boys, 7 years for Caucasian girls, and 6 years for African American girls). A. Central precocious puberty (CPP): precocity that results from premature reactivation of the hypothalamic GnRH pulse generator/pituitary gonadotropin-gonadal axis. This condition is GnRH dependent. CPP can be idiopathic or neurogenic. Figure 8. Idiopathic CPP Idiopathic CPP can be progressive and non-progressive. in boys Idiopathic progressive CPP occurs in children with no familial tendency and no signs of organic disease. In boys with idiopathic progressive CPP (Figure 8), the testes usually enlarge under gonadotropin stimulation before any other signs of puberty are seen. In girls with idiopathic progressive CPP (Figure 9), an increase in the rate of growth, the appearance of breast development, enlargement of the labia minora, and maturational changes in the vaginal mucosa are the usual presenting signs, with variable manifestations of pubic hair Figure 9. Idiopathic CPP in girls depending on the age at onset. Physiology: Puberty & Aging Reproductive System Page 9 of 13 Dr. Jeyasuria Pancharatnam B. Peripheral precocious puberty: Extra-pituitary secretion of gonadotropins or secretion of gonadal steroids independent of pulsatile GnRH stimulation. This condition leads to virilization in boys or feminization in girls, and is termed GnRH-independent sexual precocity. In most cases, pubertal development is incomplete and fertility is not attained. Example: McCune-Albright Syndrome: The classical clinical triad of McCune-Albright syndrome is precocious pubertal development, cafe-au-lait spots, and bony fibrous dysplasia (Figure 10). Precocious pubertal development is not observed in all cases and appears to be more common among girls than boys. This disorder is due to constitutive activation of the Gsα protein, and subsequent increased autonomous ovarian estrogen and testicular testosterone secretion in affected girls and boys, respectively. The syndrome is due to postzygotic somatic cell mutations in the GNAS1 gene; missense mutations Arg201His and Arg201Cys are among the most common. Figure 10. McCune-Albright Syndrome Delayed puberty is the result of delayed gonadarche and is defined as secondary sexual characteristic development at an age greater than two standard deviations more than for the normal population. Thus, for girls, lack of breast development by age 13 years or menarche by 16 years may be viewed as delayed. For boys, prepubertal testicular volume at age 14 years is considered to be delayed. Pubertal delay can be broadly sub-classified as GnRH-dependent, pituitary-dependent, and gonad-dependent. Physiology: Puberty & Aging Reproductive System Page 10 of 13 Dr. Jeyasuria Pancharatnam A. GnRH-Deficiency: This category is the consequence of absent or impaired GnRH secretion that may result from either a primary developmental anomaly of the hypothalamus or secondary pathophysiological conditions. GnRH-Deficiency can be due to gonadal failure, defects of steroidogenesis, or defects of steroid action. GnRH-Deficiency is reported to affect one in 7500 male patients, one in 70,000 female patients, and comprises a diverse group of reproductive disorders. Figure 11. Kallmann syndrome GnRH-Deficiency can be due to mutations in several genes (an oligogenic disorder) and can lead to a spectrum of reproductive, olfactory, and non- reproductive clinical features. GnRH-Deficiency has been sub-classified into three major categories: (1) Kallmann syndrome with anosmia (Figure 11); (2) hypothalamic hypogonadism without anosmia; and (3) acquired hypothalamic hypogonadism. Kallmann syndrome (KAL1 gen) is characterized by isolated gonadotropin deficiency, anosmia, X-linked inheritance, and the failure of GnRH neurons to migrate from the olfactory bulb into the hypothalamus during embryonic development (Figure 11). The inability of the hypothalamus to secrete GnRH (gonadotropin-releasing hormone) results in the failure to initiate puberty, the lack of testicular development, primary amenorrhea, and infertility (Figure 11). This syndrome is associated with hyposmia (reduced ability to smell) or anosmia (the inability to smell; Figure 11). B. Pituitary-Deficiency is due to a mutation in the gene for the GnRH-R, a mutation in a gene coding for one of the gonadotropin subunits, or a more generalized developmental anomaly of the pituitary. GnRH-R Gene Mutations. FSH-β Gene Mutations. LH-β Gene Mutations. Physiology: Puberty & Aging Reproductive System Page 11 of 13 Dr. Jeyasuria Pancharatnam C. Gonadal Deficiency: Etiologies include sex chromosome abnormalities leading to aberrant differentiation of the gonads (gonadal dysgenesis), absence of the gonads, and injury to the gonads. The hypergonadotropism associated with primary gonadal failure and with disorders of steroidogenesis or steroid hormone action is a result of loss of negative feedback inhibition by gonadal steroids at both the hypothalamic and pituitary level. Gonadal dysgenesis is used to describe disorders in which gonadal differentiation is aberrant. Gonadal dysgenesis can be due to haploinsufficiency for the X chromosome (e.g., Turner syndrome). Other forms may result from mutations in genes involved in the process of sexual differentiation. Turner syndrome is due to deletions or structural rearrangements of the X chromosome. The reported incidence of live born females with this form of gonadal dysgenesis is 1:2000 to 1:5000. Dr. Henry Turner defined this syndrome as “A syndrome of infantilism, congenital webbed neck and cubitus valgus” (Figure 12) The majority of girls with Turner syndrome do not Figure 12. Turner Syndrome spontaneously enter puberty. Girls with Turner syndrome tend to have normal verbal abilities. As a group, however, they demonstrate specific deficits in visuospatial processing, visuoperceptual skills, motor function, and nonverbal memory compared with normal girls. These deficits may be associated with one or more deletions of a critical region in the pseudoautosomal region of the X chromosome. The diagnostic tests for Turner syndrome include: prenatal diagnosis based on ultrasound (cystic higroma) and chromosomal karyotype (amniocentesis). The growth deficit of girls with Turner syndrome can be partially ameliorated by growth hormone treatment. Estrogen replacement therapy is generally necessary to induce pubertal development. Yet, uterine maturation may be incomplete and may contribute to a high rate of miscarriage in both spontaneous and assisted pregnancies among women with Turner syndrome. Physiology: Puberty & Aging Reproductive System Page 12 of 13 Dr. Jeyasuria Pancharatnam MENOPAUSE: A CONSEQUENCE OF AGING IN WOMEN There are about 6-7 million germ cells in the ovary at 20 weeks of gestation. At birth this number drops to 1-2 million and at puberty the number is at 400,000 (Average 12,5 years of age in girls). The average age of menopause is about 51.5 years. It is estimated that in a woman’s reproductive lifespan she produces 400 oocytes and at menopause the number of follicles is reduced to almost nothing and most of this loss from 400,000 is due to atresia. This loss of the pool of follicles causes the ovaries to no longer respond to gonadotropins and the levels of GnRH, LH and FSH rise. There are subtle changes in the flow and length menstrual cycle later in reproductive age. As early as age 35 we can see FSH levels rise. A perimenopausal stage is represented by changes and variation in menstrual cycle periods of greater than 7 days. This is followed by longer interval of greater than 60 days and we are into what is termed the menopausal transition. This transition last from 1-3 years which is marked by a loss of estrogen as the transition takes place due a loss in granulosa cells (the ovary has a prominent stroma and there are fewer primary, secondary and antral follicles). Because of the loss of follicle with aging the levels of estrogens, inhibins and progestins decrease causing the negative feedback at the hypothalamic pituitary level to be lost and thus FSH levels rise. (See Figure 13)Another granulosa cell product that is not involved in feedback but may be a good gauge of follicle number and ovarian function is AMH (anti-mullerian hormone). AMH levels fall as the ovary ages and may be a marker of the perimenopause and the menopause transitional period. Generally the reproductive success in women declines at age 35 as egg quality decreases with age. It is possible to lengthen the period of reproductive success through IVF. The success rate with frozen embryos is very good but requires that the woman utilize a sperm donor to produce an in vitro embryo. Freezing eggs is experimental but shows great promise. Women can also have successful pregnancies with donated eggs from younger women. Figure 13: Changes in gonadotropin and ovarian hormone production associated with aging. Lower levels of inhibin B and estradiol result in impaired negative feedback regulation of gonadotropin release, increasing follicle- stimulating hormone (FSH) and luteinizing hormone (LH). Production of androstenedione and testosterone during early menopause continues, with some conversion to estradiol by aromatase activity in adipose tissue. Adrenal- derived androstenedione is converted to estrone, principally in adipose tissue. DHEA, dehydroepiandrosterone; GnRH, gonadotropin- releasing hormone. Physiology: Puberty & Aging Reproductive System Page 13 of 13 Dr. Jeyasuria Pancharatnam ANDROPAUSE: A CONSEQUENCE OF AGING IN MEN As men age there is a general attrition of the Leydig cell population, which causes a loss of testosterone production. Although aging in men does not cause a sudden cessation of reproductive function as seen in women there is a general decline with aging of testosterone decline. Aging causes sexual dysfunction, bone loss, fatigue, cognitive decline and mood changes which all can be attributed to hormonal loss. These are all symptoms of organic hypogonadism but also a consequence of aging. The GNRH pulse generator also slows down with age and thus causes a decrease in LH production. This age related hypogonadism is often referred to as “andropause” and late onset hypogonadism (LOH). There is a growing interest in testosterone replacement therapy due to this condition. There is a robust campaign to use testosterone by pharmaceutical companies though there is still a lack of understanding as to the outcomes of this therapy and the added danger of accelerating conditions such as prostate cancer. There should also be a better understanding of LOH vs organic hypogonadism (e.g klinefelters, pituitary tumor, kallman syndrome) when testosterone treatment is suggested.