Endocrinology - Reproductive Endocrinology Flashcards
What is the default pattern of genital development? What is required for male development to occur?
In humans, female is the default pattern of development. There are 3 important steps in sexual differentiation and development of the male phenotype:
1) Differentiation of a bipotential priordial gonad (identical in both XX and XY fetuses) into testes that secrete testosterone
2) Development of the internal reproductive tract. In males this requires the presence of anti-Mullerian hormone (AMH) that causes involution of the Mullerian ducts
3) Development of external genitalia that require testosterone or 5-DHT
Female differentiation occurs in the absence of these hormones.
Describe the first level of sexual differentiation
The first level of sexual differentiation is the establishment of chromosomal sex. Most infants are 46,XX females or 46,XY males. Genetic sex determines gonadal sex. Gonadal structures differentiate from the “bipotential,” or primordial, gonadal ridge. The Y chromosome contains an area known as the sex-determining region, or SRY. The SRY gene product initiates the differentiation of the bipotential gonad into a testis. In its absence, the gonad becomes an ovary.
What is the next level of sexual differentiation?
The next level of sex determination involves the genital duct structures. The genital duct structures are initially identical in the male and female. In the normal male, testicular Leydig cells produce testosterone, which is necessary to maintain ipsilateral wolffian duct structures (e.g., vas deferens, epididymis, seminal vesicles). The Sertoli cells of the testis produce müllerian-inhibiting factor (MIF), which acts ipsilaterally to cause regression of müllerian duct structures (fallopian tubes, uterus, upper third of the vagina). In the absence of testosterone and MIF, müllerian duct structures are preserved, and wolffian duct structures regress.
Describe development of the external genitalia?
Male and female external genitalia arise from the same embryologic structures. In the absence of androgen stimulation, these structures remain in the female pattern, whereas the presence of androgens causes male differentiation (virilization). For complete virilization, testosterone must be converted to dihydrotestosterone (DHT) by the enzyme 5-alpha-reductase, and androgen receptors must be functional. Excessive androgens virilize a female. Inadequate androgen production, inability to convert testosterone to DHT, or inability to respond to androgens, as in androgen receptor defects, results in undervirilization of a male.
Describe the Lyon hypothesis. In which cells are two X chromosomes necessary for development?
Dr. Mary Lyon addressed the question of the extra X chromosomal material in females. Simply put, if two X chromosomes are necessary in each cell, how can males be developmentally normal? Lyon suggested that in each cell, one of the two X chromosomes is inactive, and in any given cell line, which X is active is randomly determined. In fact, the inactive X may be identified in many cells as a clump of chromatin at the nuclear membrane (Barr body). The important exception is in the ovary, where two functional X chromosomes are necessary for normal sustained ovarian development. Without two X chromosomes per cell (as in 45 XO Turner syndrome), the ovary involutes and leaves only fibrous tissue.
Describe normal male sexual differentiation
The fetus is sexually bipotential. The undifferentiated gonad is derived from coelomic epithelium, mesenchyme, and germ cells, which, in the presence of SRY, give rise to Leydig cells, Sertoli cells, seminiferous tubules, and spermatogonia. Testes are formed at 7 weeks. Testicular production of testosterone (Leydig cells) leads to wolffian duct development, whereas MIF (Sertoli cells) leads to müllerian duct regression. Masculinization of the external genitalia is mediated by DHT, which is produced from testosterone by the action of the enzyme 5-alpha-reductase.
Describe normal female sexual differentiation
In the absence of SRY, the undifferentiated gonad gives rise to follicles, granulosa cells, theca cells, and ova. Ovarian development occurs in the thirteenth to sixteenth week of gestation. Lack of testosterone and MIF allows regression of the wolffian ducts and maintenance of the müllerian ducts, respectively. Lack of DHT results in the maintenance of female external genitalia.
How is external genital development determined?
The external genitalia arise from the urogenital tubercle, urogenital swelling, and urogenital folds. In females, these become the clitoris, labia majora, and labia minora, respectively. In males, under the influence of DHT, the genital tubercle becomes the glans of the penis, the urogenital folds elongate and fuse to form the shaft of the penis, and the genital swellings fuse to form the scrotum. Fusion is completed by 70 days of gestation, and penile growth continues to term.
Female differentiation does not require ovaries or hormonal influence, whereas normal development of male genitalia requires normal testosterone synthesis, conversion to DHT by 5-alpha-reductase, and normal androgen receptors.
The differential diagnosis of disorders of sexual differentiation (DSD) is complex, but it may be simplified by an approach based on an understanding of the process of sexual differentiation. Can you devise such a classification?
1) Sex chromosome DSD - e.g. Turner’s 45X, Klienfelter’s 45XXY etc
2) 46 XY DSD - e.g. disorders of testicular development, disorders or androgen biosynthesis, complete or partial androgen insensitivity, LH receptor deficiency, disorders of anti-Mullerian hormone receptor
3) 46 XX DSD - e.g. disorders of ovarian development, androgen excess (e.g. foetal - congenital adrenal hyperplasia; maternal - ovarian tumour, exogeneous)
What is a virilized female?
A virilized female (previously called female pseudohermaphroditism) is characterized by a 46,XX karyotype, ovaries, normal müllerian duct structures, absent wolffian duct structures, and virilized genitalia resulting from exposure to androgens during the first trimester.
What is the most common cause of a virilized female?
The most common cause is congenital adrenal hyperplasia (CAH) resulting from 21-hydroxylase deficiency. In fact, this disorder is the single most common cause of sexual ambiguity. In this condition, the gene responsible for encoding the 21-hydroxylase enzyme is inactive. This enzyme blockage occurs along the pathway to cortisol and aldosterone. Because of low or absent levels of cortisol, the feedback mechanism produces increased adrenocorticotropic hormone (ACTH), which drives the pathway further and results in accumulation of precursor hormones, the measurement of which is useful for making a diagnosis. Increased ACTH also drives the production of excess adrenal androgens, which result in virilization. Virilization may also be caused by maternal ingestion of androgens or synthetic progesterones during the first trimester of pregnancy.
How do virilized females present?
Affected infants may present with a wide spectrum of ambiguity, ranging from clitoromegaly alone to complete fusion of the labial swellings to form a scrotum and large phallus. (Beware the infant with bilaterally undescended testes.) Even in the most virilized girls, a penile urethra is rare.
What is an undervirilized male?
An undervirilized male (previously called male pseudohermaphroditism) refers to a 46,XY male who has ambiguous or female external genitalia. The abnormality may range from hypospadias to a completely female phenotype. Such disorders result from deficient androgen stimulation of genital development and most often are secondary to Leydig cell agenesis, testosterone biosynthetic defects, 5-alpha-reductase deficiency, and partial or total androgen resistance (androgen receptor defects).
What is gonadal dysgenesis?
Patients with Y-related chromosomal or genetic disorders that cause maldevelopment of one or both testes are said to have gonadal dysgenesis. They present with ambiguous genitalia and may have hypoplasia of wolffian duct structures and inadequate virilization. MIF may be absent, thus allowing müllerian duct structures to persist. Duct asymmetry is therefore common. The Y-containing dysgenetic testes are at risk for developing gonadoblastomas and must be removed.
What is complete androgen insensitivity?
The androgen receptor, encoded on the X chromosome, binds testosterone and, more avidly, DHT. Androgen insensitivity results from abnormalities of the androgen receptor. Complete androgen resistance occurs with a frequency of 1 in 20,000 to 1 in 64,000 XY individuals.
How do infants with complete androgen insensitivity present?
Complete androgen insensitivity (testicular feminization) rarely manifests as ambiguity in the newborn period or early childhood. Unless the testes have descended and are palpable in the labia majora, affected infants appear as phenotypically normal females.
Affected children grow as normal females until puberty. They feminize with normal breast development at puberty because high levels of testosterone are aromatized to estrogen, but they have no pubic or axillary hair and no menses. Because they produce MIF, they lack müllerian duct structures. Wolffian duct structures are also rudimentary or absent because these patients lack normal testosterone receptors. Gender identity is usually female. Patients come to medical attention because of primary amenorrhea. The diagnosis is therefore frequently made when patients are in their middle to late teens.
Summarize the physiologic results of 5-alpha-reductase deficiency.
Deficiency of 5-alpha-reductase impairs the conversion of testosterone to DHT and leads to incomplete virilization and differentiation of the external genitalia, which are dependent on the action of DHT. The disorder is particularly well documented in large kindreds in the Dominican Republic and Gaza, in whom it is inherited as an autosomal recessive condition.
Describe the clinical picture in children with 5-alpha-reductase deficiency.
Male infants with 5-alpha-reductase deficiency are born with sexual ambiguity. External genitalia range from a penis with simple hypospadias to a blind vaginal pouch and clitoris-like phallus. The most common presentation is a urogenital sinus with a blind vaginal pouch. During puberty, affected boys undergo virilization; affected females are normal.
Traditionally, infants with 5-alpha-reductase deficiency were raised as females until puberty, then continued life as males, and, in some cases, achieved fertility. More recently, however, the condition has been recognized early in life, and affected males are now raised from infancy as boys.
What physiologic events initiate puberty?
Reactivation of the hypothalamic-pituitary-gonadal axis initiates puberty. Several neurotransmitters, including kisspeptin, stimulate the hypothalamic secretion of gonadotropin-releasing hormone (GnRH) in pulses during sleep and eventually during waking hours as well. GnRH pulses stimulate the pituitary gland to secrete pulses of gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), of which there is an LH predominance. In response to the increased secretion of gonadotropins, increased secretion of gonadal hormones leads to the progressive development of secondary sexual characteristics and gametogenesis. In both sexes, puberty requires maturation of gonadal function and increased secretion of adrenal androgens.
How is pubertal development measured?
Sexual maturity is determined by physical examination and is described in a scale devised by John Tanner in 1969. Because of the distinct actions of adrenal androgens and gonadal steroids, it is important to distinguish between pubic hair and breast development in girls and between pubic hair and testicular development in boys. In all cases, Tanner stage I is prepubertal and Tanner stage V is complete maturation. In addition to the physical examination, the tools to assess pubertal development may include determination of bone age, growth velocity, growth pattern, and specific endocrine studies.
What is adrenarche?
Adrenarche refers to the time during puberty when the adrenal glands increase their production and secretion of adrenal androgens. Plasma concentrations of dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S), the most important adrenal androgens, begin to increase in children by approximately 6 to 8 years. However, the signs of adrenarche, such as pubic hair, axillary hair, acne, and body odor do not typically occur until early puberty to midpuberty. The control of adrenal androgen secretion is not clearly understood, but it appears to be separate from GnRH and the gonadotropins.
What controls the pubertal growth spurt?
n both boys and girls, the pubertal growth spurt is primarily controlled by the gonadal steroid estrogen. In both sexes, gonadal (and adrenal) androgens are aromatized to estrogens. Estrogens augment growth hormone (GH) and insulin-like growth factor I (IGF-I) secretion. Estrogens also suppress osteoclast activity and prolong the life span of osteoblasts and osteocytes. Androgens have a small independent role in maintenance of adequate bone mineral density. At the end of puberty, linear growth is nearly complete as a result of the effects of gonadal steroids on skeletal maturation and epiphyseal fusion.
What is the normal pattern of puberty in boys?
The mean age of puberty onset in boys is 11.8 years, with a range of 9 to 14 years. Black boys may start puberty as early as 8 years of age. The first evidence of puberty in the majority of boys is enlargement of the testes to a volume greater than 4 mL or a length greater than 2.5 cm. It is not until midpuberty, when testosterone levels are rapidly rising, that boys experience voice change, axillary hair, facial hair, and the peak growth spurt. Spermatogenesis is mature at a mean age of 13.3 years.
What is the normal pattern of puberty in girls?
Girls normally begin puberty between age 8 and 13 years (mean age: 10.4 years for white girls, 9.8 years for Hispanic girls, and 9.5 years for black girls). The initial pubertal event is typically the appearance of breast buds, although a small percentage of girls will develop pubic hair first. In an even smaller percentage of girls, menstrual cycling may appear first. Initial breast development often occurs asymmetrically and should not be of concern. Breast development is primarily under the control of estrogens secreted by the ovaries, whereas growth of pubic hair and axillary hair results mainly from adrenal androgens. Unlike in boys, the pubertal growth spurt in girls occurs at the onset of puberty. Menarche usually occurs 18 to 24 months after the onset of breast development (mean age: 12.5 years). Although most girls have reached about 97.5% of their maximum height potential at menarche, this can vary considerably. Consequently, age of menarche is not necessarily a good predictor of final adult height.
What constitutes sexual precocity in boys and girls?
Precocious puberty is defined as pubertal development occurring below the limits of age set for normal onset of puberty. In girls, this is puberty before 8 years in white girls, 6.6 years in black girls, and 6.8 years in Hispanic girls. For boys, precocious puberty is development occurring before 9 years in white and Hispanic boys and 8 years in black boys. Girls showing signs of puberty between 6 and 8 years often have a benign, slowly progressing form that requires no intervention. Consequently, evaluation and treatment of girls who start puberty between 6 and 8 years should depend on factors such as family history, rapidity of development, the presence of central nervous system (CNS) symptoms, and family concern. Girls who are short and start puberty between 6 and 8 years may also benefit from evaluation. In children who present with early pubertal signs, precocious puberty must be distinguished from normal variants of puberty, such as benign premature thelarche and benign premature adrenarche.
What clinical findings are associated with precocious puberty?
Precocious puberty, regardless of the cause, is associated with accelerated linear growth and skeletal maturation secondary to elevated sex steroid levels. Children with precocious puberty are often tall for their age during childhood. However, skeletal maturation may become more advanced than stature, thus leading to premature fusion of the epiphyseal growth plates and a compromised final adult height. In addition to the physical consequences of early puberty, social and psychological aspects may need to be considered.
