Flashcards in Endocrinology - Reproductive Endocrinology Deck (65):
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.
In which sex is precocity more prevalent?
Precocious puberty predominantly affects girls. The disparity in overall prevalence of precocity is explained by the large numbers of girls with central idiopathic precocity, a condition that is less common in boys. At least 80% of all precocious puberty in girls is central idiopathic. The prevalence of organic causes of precocious puberty (CNS lesions, gonadal tumors, and specific underlying diseases) is similar in both sexes.
How is a diagnosis of precocious puberty made?
The diagnosis of precocious puberty requires the appearance of the physical signs of puberty before the defined age limits, as discussed previously. In both boys and girls, a complete history should be taken, with careful consideration of any exposure to exogenous steroids or estrogen receptor agonists (e.g., lavender oil or tea tree oil), onset of pubertal signs and rate of progression, presence or history of CNS abnormalities, and pubertal history of other family members. Height measurements should be plotted on a growth chart to determine growth pattern and growth velocity. A physical examination should be performed with a focus on Tanner staging, the presence of café-au-lait spots, and neurologic signs. One of the early steps in evaluating a child with early pubertal development should be to obtain a radiograph of the left hand and wrist to determine skeletal maturity (bone age). If the bone age is advanced, further evaluation is warranted. Sex steroid levels should be measured, especially in boys, because testosterone levels higher than the prepubertal range (> 10 ng/dL) confirm pubertal status. For girls, estradiol measurements are less reliable indicators of puberty, because most commercial assays are not sufficiently specific or sensitive to demonstrate an increase during early puberty.
At what age does failure to enter puberty necessitate investigation?
Delayed puberty should be evaluated if there are no pubertal signs by 13 years in girls and by 14 years in boys. An abnormality in the pubertal axis may also manifest as a lack of normal pubertal progression, which is defined as more than 4 years between the first signs of puberty and menarche in girls or more than 5 years for completion of genital growth in boys.
When is hypogonadism diagnosed?
Functional or permanent hypogonadism should be considered when there are no signs of puberty and bone age has advanced to beyond the normal ages for puberty to start. A eunuchoid body habitus is often evident in children with abnormally delayed puberty; a decreased ratio of upper to lower body and a long arm span characterize this habitus. As a rule, serum gonadotropin levels are measured first to determine whether the child has hypogonadotropic hypogonadism (gonadotropin deficiency) or hypergonadotropic hypogonadism (primary gonadal failure). If a child’s bone age is less than the normal age for puberty to start, gonadotropin levels are not a reliable means of making an accurate diagnosis.
What are the causes of hypogonadotropic hypogonadism?
Normal or suppressed gonadotropins indicate a failure of the pituitary to stimulate gonadal steroid production. Chronic illness, malnutrition, excessive exercise, or anorexia can cause a functional deficiency of gonadotropins that reverses when the underlying condition improves. Hyperprolactinemia can also manifest as delayed puberty, and only 50% of the time will there be a history of galactorrhea. Other endocrinopathies such as diabetes mellitus, glucocorticoid excess, and hypothyroidism can cause hypogonadotropic hypogonadism when untreated. Permanent gonadotropin deficiency is suspected if these conditions are ruled out and gonadotropin levels are low. Gonadotropin deficiency may be associated with other pituitary deficiencies from conditions such as septo-optic dysplasia, tumors such as craniopharyngioma, trauma, empty sella syndrome, pituitary dysgenesis, Rathke pouch cysts, or cranial irradiation. Various syndromes, such as Kallmann syndrome, Laurence-Moon-Bardet-Biedl syndrome, and Prader-Willi syndrome are also associated with gonadotropin deficiency, so a karyotype or other genetic testing may be necessary. Drug abuse, particularly with heroin or methadone, has been associated with hypogonadotropic hypogonadism. Isolated gonadotropin deficiency (i.e., occurring without another pituitary deficiency) is often difficult to diagnose because hormonal tests do not absolutely distinguish whether a child can produce enough gonadotropins or whether he or she simply has very delayed puberty. If gonadotropin deficiency cannot be clearly distinguished from delayed puberty, a short course of sex steroids can be given. Patients with constitutional delay often enter puberty after such an intervention. If spontaneous puberty does not occur after this treatment or after a second course, the diagnosis of gonadotropin deficiency may be made.
What are the causes of hypergonadotropic hypogonadism?
Elevated gonadotropin levels indicate a failure of the gonads to produce enough sex steroids to suppress the hypothalamic-pituitary axis. These levels are diagnostic for gonadal failure at two periods of time: before 2 to 3 years of age and after the bone age is at or beyond the normal age for puberty to start. If hypergonadotropic hypogonadism is diagnosed, a karyotype should be performed. Potential causes include the following:
Variants of ovarian or testicular dysgenesis: Turner syndrome, Klinefelter syndrome, Noonan syndrome, pure XX or XY gonadal dysgenesis
Gonadal toxins: chemotherapy (particularly alkylating agents), radiation treatment
Androgen enzymatic defects: 17-alpha-hydroxylase deficiency in the genetic male or female, 17-ketosteroid reductase deficiency in the genetic male
Complete or partial androgen insensitivity syndrome
Galactosemia (in girls only)
Other miscellaneous disorders: infections, gonadal autoimmunity, vanishing testes, trauma, surgery, torsion
What is Klinefelter syndrome?
Klinefelter syndrome is the most common cause of testicular failure and results from at least one extra X chromosome; the most common karyotype is 47,XXY. The incidence is 1 in 1000 male births, and eunuchoid body proportions are often present from early childhood. Associated features include gynecomastia, tall stature, small testes, low testosterone, and elevated serum gonadotropins. Learning disabilities and behavioral problems may also be present. Many boys with Klinefelter syndrome have spontaneous onset of pubic hair growth, but they fail to progress completely through puberty. Testosterone supplementation is indicated in many boys over time, and in some it is required to initiate puberty. Leydig cell function (testosterone production) is variable, but seminiferous tubular function is almost always abnormal. This generally results in infertility, and many of these men are not diagnosed until they are seen in an infertility clinic.
What is Turner syndrome?
Any consideration of pubertal delay in girls must include the possibility of Turner syndrome. An absent or structurally abnormal second X chromosome characterizes Turner syndrome. The incidence of Turner syndrome is approximately 1 in 2000 live female births. However, the chromosomal abnormality is actually more common than this. Ninety percent or more of conceptuses with Turner syndrome do not survive beyond 28 weeks of gestation, and the 45,XO karyotype occurs in 1 out of 15 miscarriages. In the absence of a second functional X chromosome, oocyte degeneration is accelerated, leaving fibrotic streaks in place of normal ovaries. Because of primary gonadal failure, serum gonadotropin levels rise and are elevated at birth and again at the normal time of puberty.
What is amenorrhea?
A girl who has not had menarche by 16 years of age, or within 4 years after the onset of puberty, is considered to have primary amenorrhea. Secondary amenorrhea is diagnosed if more than 6 months have elapsed since the last menstrual period, or if more than the length of three previous cycles has elapsed with no menstrual bleeding.
How do you evaluate a girl with amenorrhea?
To sort out the many causes of amenorrhea, it is helpful to distinguish girls who produce sufficient estrogen from those who do not by performing a progesterone challenge. Girls who are producing estrogen will have withdrawal bleeding after 5 to 10 days of oral progesterone, whereas those who are estrogen-deficient will have very little or no bleeding. Those who do not have bleeding should be evaluated for hypogonadism as described previously. However, in two situations, girls who have sufficient estrogen will not have withdrawal bleeding: obstruction of the cervix and absence of the cervix or uterus. In Rokitansky syndrome, maldevelopment of the müllerian structures leads to an absent or hypoplastic uterus or cervix (or both). Complete androgen insensitivity syndrome (testicular feminization) in a genetic male results in a phenotypic female who has normal breast development because of the aromatization of testosterone to estrogen. The production of antimüllerian hormone in patients with androgen insensitivity syndrome leads to regression of the müllerian structures and thus the absence of a uterus. The absence of a cervix is a diagnostic finding in both Rokitansky syndrome and complete androgen insensitivity syndrome. Consequently, a pelvic examination should be considered in all girls who present with amenorrhea, especially primary amenorrhea.
What causes amenorrhea in girls who are producing estrogen and do not have an outflow tract obstruction?
Amenorrhea in girls who are producing normal or even elevated amounts of estrogen is a manifestation of anovulatory cycles. Irregular menses may also be a sign of chronic anovulation given that estrogen production, unopposed by progesterone, leads to endometrial hyperplasia and intermittent shedding. Because menarche is normally followed by a period of anovulatory cycles and irregular menses, many adolescents with a pathologic cause of amenorrhea may be missed. Consequently, it is important to evaluate all girls who do not have regular menses by 3 years after menarche. The most common cause of chronic anovulation is polycystic ovarian syndrome (PCOS), a disorder characterized by increased ovarian androgen production. The clinical presentation of PCOS varies and may include amenorrhea, oligomenorrhea, dysfunctional uterine bleeding, hirsutism, acne, or obesity.
What is male hypogonadism?
Male hypogonadism is the clinical and/or laboratory syndrome that results from a failure of the testis to work properly. The normal testis has two functions: synthesis and secretion of testosterone from the Leydig cells and production of sperm from the seminiferous tubules. Deficiency of one or both functions is termed male hypogonadism. This condition can result from a disruption at one or more levels of the hypothalamic-pituitary-gonadal axis. Depending on the stage of development, hypogonadism may have varied manifestations.
What are the manifestations of in utero hypogonadism?
In utero androgen deficiency leads to a female phenotype or ambiguous genitalia, most commonly caused by a block in the production of testosterone secondary to congenital testosterone biosynthetic enzyme defects. Rarely, peripheral tissues cannot respond normally to testosterone, thereby resulting in the androgen insensitivity syndromes of testicular feminization (complete) and Reifenstein’s syndrome (incomplete). Other manifestations include micropenis, hypospadias, and cryptorchidism.
What are the manifestations of peripubertal hypogonadism?
Childhood androgen deficiency results in delayed, incomplete, or absent pubertal development. Common manifestations include the following:
Eunuchoid proportions (ratio of pubis to vertex/pubis to floor is < 0.9 and/or arm span is > 5 cm more than height; this phenotype results from the delayed closure of the epiphyses)
Small testes (< 20 mL or < 4.5 × 3.0 cm)
Decreased body hair
Reduced peak bone mass
Reduced male musculature
Persistently higher-pitched voice
What are the manifestations of hypogonadism in early adulthood?
In early adulthood, a decrease in sperm output (azoospermia or oligospermia) without deficient production of testosterone is common and results in male infertility; thus, infertility is a form of male hypogonadism. A decrease in production of testosterone in adulthood is usually accompanied by a decline in production of sperm. When it is not, the term fertile eunuch (eunuchoid proportions, low levels of luteinizing hormone [LH], low levels of testosterone, normal levels of follicle-stimulating hormone [FSH], and spermatogenesis) is appropriately applied. Libido and/or potency may be diminished.
What are the manifestations of hypogonadism in middle to late adulthood?
The most frequent circumstance in which adult hypogonadism occurs is in the middle-aged or senescent man complaining of decreased libido or potency. Semen analysis is rarely performed in these men because they are usually not concerned with fertility. Other findings may include osteoporosis, diminished androgen production, and small prostate. If the onset of hypogonadism is acute, the patient may experience hot flushes and sweats.
How is the production of testosterone normally regulated?
LH is episodically secreted from the anterior pituitary in response to pulses of gonadotropin-releasing hormone (GnRH), thus stimulating production of testosterone by Leydig cells. Once testosterone is secreted into the bloodstream, it is bound by sex hormone–binding globulin (SHBG) and albumin. The non–SHBG-bound (or “free”) testosterone provides negative feedback to the hypothalamic-pituitary unit and thus inhibits output of LH. This classic endocrine feedback loop serves to maintain serum testosterone at a predetermined level; if serum testosterone falls below the set point, the pituitary is stimulated to secrete LH, which, in turn, stimulates testicular output of testosterone until serum levels return to the set point. Conversely, if serum testosterone rises above the set point, decreased output of LH results in decreased testicular output of testosterone until serum levels have declined to the set point. Although most automated total testosterone assays are reliable and are generally able to distinguish hypogonadal from eugonadal men, abnormalities in the SHBG level may give falsely low or high total testosterone levels. Equilibrium dialysis is the gold standard for measuring the free testosterone, but it is not commonly available and should be ordered to be performed only in a reliable reference laboratory. Liquid chromatography–mass spectrometry or gas chromatography–mass spectrometry is used by some reference laboratories to measure testosterone. This is a very accurate but expensive method. Analog methods for determining free testosterone are more widely available but are not accurate in the low ranges.
What are some conditions associated with decreased or increased serum SHBG levels?
Moderate obesity, nephrotic syndrome, hypothyroidism, and the use of certain medications (notably glucocorticoids and androgenic steroids) decrease SHBG levels and give a low total serum testosterone level, whereas aging, anticonvulsant use, estrogen use, herbal preparations for “prostate health” that contain plant-derived estrogens, hepatic cirrhosis, human immunodeficiency virus (HIV) infection, and hyperthyroidism may all increase SHBG and cause a high total level of testosterone.
What is the difference between primary and secondary hypogonadism?
Failure of testicular function may result from a defect either at the testis or at the hypothalamic-pituitary level. Testicular disorders leading to hypogonadism are termed primary hypogonadism, whereas disorders of hypothalamic-pituitary function leading to hypogonadism are termed secondary hypogonadism. This distinction has therapeutic implications. In men with secondary hypogonadism, fertility can generally be restored with appropriate hormonal treatment. Men with primary hypogonadism have fewer options and more limited success with improvement in fertility. In addition, the evaluation of secondary hypogonadism can reveal a pituitary mass or systemic illness as the underlying cause.
What is the initial laboratory workup for hypogonadism?
Primary hypogonadism resulting from a testicular disorder leads to a decline in production of testosterone and sperm, a consequent decrease in the negative feedback effects on the pituitary, and a corresponding increase in serum levels of LH and FSH. Conversely, in secondary hypogonadism resulting from a hypothalamic-pituitary disorder, serum LH and FSH may be subnormal or “inappropriately” normal (explainable, in part, by decreased bioactivity) despite a low testosterone level. A subnormal sperm count and a normal testosterone level with a normal LH and elevated FSH suggest primary hypogonadism with a dysfunction of the seminiferous tubules and sperm production but intact Leydig cell function.
Define erectile dysfunction?
The inability to obtain and maintain an erection sufficient for sexual intercourse. ED is usually multifactorial in etiology, and most men have at least some psychogenic factors that contribute to the disorder (i.e., performance anxiety can exacerbate underlying organic etiology).
List the six main categories of ED
1)Hormonal: Hypogonadism (primary or secondary), hyperprolactinemia (with resultant hypogonadism), hyperthyroidism or hypothyroidism, diabetes, adrenal insufficiency, and Cushing's syndrome.
2) Pharmacologic: Many causative medications such as antihypertensives (clonidine, beta blockers, vasodilators, thiazide diuretics, spironolactone); antidepressants (SSRIs, TCAs); antipsychotics; anxiolytics, cimetidine; phenytoin; carbamazepine; ketoconazole; metoclopramide; digoxin; alcohol; and, illicit drugs (marijuana, cocaine, and heroin).
3) Systemic disease: Any severe illness that leads to hypogonadotrophic hypogonadism.
4) Vascular: Diabetes, peripheral arterial disease.
5) Neurologic: Diabetes, spinal cord injury, neuropathy.
6) Psychogenic: Uncommon in isolation, but contributes to most cases owing to other etiologies and should be considered a diagnosis of exclusion.
What are the most important steps in the management of ED?
Identifying and treating organic etiologies and discontinuing any offending medications, if possible.
What are the potential treatment options for men with ED?
Correction of any hormonal abnormality, such as testosterone replacement for hypogonadism, correction of thyroid dysfunction, maximal glycemic control in diabetes, and treatment of hyperprolactinemia with dopamine agonist.
Treatment of any underlying systemic disorders, including depression, but note that, although SSRIs can cause ED, SSRIs may help to prevent premature ejaculation.
Mechanical devices including rings, vacuum pump device that may be cumbersome to some patients, but have minimal side effects.
Surgical interventions, typically used as a last resort and include revascularization, removal of venous shunts, and penile implants.
Supportive counseling and/or couples therapy.
What medical therapies are available for ED?
Alpha2 adrenergic receptor blocker: yohimbine (oral).
Phosphodiesterase 5 inhibitors: sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis). All three are administered orally, but none should be used in combination with nitrates.
Intracavernosal injections of vasodilating medications: alprostadil (Caverject), prostaglandin E1, papaverine, and phentolamine.
Transurethral alprostadil suppositories (Muse).
List the three etiologic categories of gynecomastia.
Idiopathic, physiologic, and pathologic.
List the physiologic changes that occur throughout the life cycle that may lead to gynecomastia.
Newborn: Owing to fetal exposure to maternal estrogens during pregnancy.
Puberty: Owing to increased estrogen-to-androgen ratio.
Older ages: Likely due to combined effect of decreasing testosterone with age and increased estrogen owing to peripheral aromatization of androgens to estrogens in adipose tissue, but the exact mechanism is unclear.
What causes pathologic gynecomastia?
Usually, estrogen excess from either overproduction or peripheral aromatization including:
1) Drugs that increase estrogen activity or production or reduce testosterone activity or production.
2) Tumors that increase human chorionic gonadotropin (hCG) or estrogen production, such as testicular tumors (Leydig cell, Sertoli cell, germ cell, and granulosa cell), choriocarcinomas, and adrenal tumors. Male breast cancer is an uncommon cause.
3) Decreased androgens or androgen resistance as found in hypogonadism due to any cause such as Klinefelter's syndrome (male with extra X chromosome) and Kallmann's syndrome (hypogonadotropic hypogonadism with absent sense of smell).
4) Increased activity of enzyme that catalyzes estrogen production (aromatase) that is found in obesity, hyperthyroidism, and certain genetic mutations.
5) Displacement of estrogens from sex hormone–binding globulin.
6) Other illnesses such as end-stage liver disease, renal disease, human immunodeficiency virus (HIV) infection, familial syndromes, and starvation refeeding.
How does one begin to evaluate the causes of amenorrhea?
First, determine whether amenorrhea is primary (the patient has never had menses) or secondary (cessation of menses after she has started). Next, rule out pregnancy as a cause of amenorrhea. After pregnancy is ruled out, consider the following four broad categories of amenorrhea:
i) Anatomic/outflow tract defect
ii) Ovarian failure
iii) Hypogonadotropic hypogonadism (pituitary or hypothalamic failure)
iv) Chronic anovulation
Give examples of anatomic/outflow tract defects.
Asherman's syndrome (amenorrhea due to uterine adhesions)
Sexual differentiation disorders
What are the causes of primary ovarian failure?
Genetic alterations (Turner's syndrome with XO genotype)
LH or FSH receptor or postreceptor defects
Physical insults (radiation, chemotherapy, viral infection, oophorectomy)
Levels of FSH and LH are generally high in these disorders (hypergonadotrophic hyogonadism).
List the causes of hypogonadotropic hypogonadism.
Hypothalmic dysfunction (induced by exercise or eating disorders)
Pituitary dysfunction (such as tumors and hypopituitarism)
Androgen excess (due to adrenal tumors, PCOS, tumors with high human choriogonadotropin, and congenital adrenal hyperplasia)
Thyroid dysfunction (hyperthyroidism and hypothyroidism)
Systemic illness (such as liver and renal disease)
Levels of FSH and LH are generally low in these disorders.
Also known as “Stein-Leventhal syndrome,” PCOS is characterized by (1) oligo- or anovulation, (2) hyperandrogenism, and (3) polycystic ovaries. Patients can be diagnosed with PCOS if they have at least two of the three classic features and other etiologies have been excluded.
How do women with PCOS typically present?
With menstrual dysfunction, hirsutism, and insulin resistance. Long-term consequences of PCOS include increased risk of developing type 2 DM, hyperlipidemia, and endometrial cancer.
Describe the management of PCOS
Correction of the underlying metabolic disorder and addressing cosmetic concerns related to hirsutism. Weight loss and treatment of insulin resistance with thiozolidenediones or metformin are recommended. Oral contraceptives are used to regulate menstrual cycles and suppress hyperandrogenism. Because most patients have impaired ovulation, fertility must also be addressed. Most women can be treated with the ovulation-induction drug clomiphene citrate, either alone or in combination with insulin-sensitizing medication. Hirsutism is treated by suppressing androgen production with oral contraceptives, androgen receptor blockers, or 5-alpha-reductase inhibitors and appropriate cosmetic treatments.
Summarize the traditional rationale behind hormonal treatment of menopausal women.
Menopause represents the time in a woman's life that cyclic ovarian function ceases. Hormone replacement therapy (HRT), which consists of combined estrogen and progesterone in women with an intact uterus and estrogen only for women without a uterus, has become extremely controversial over the past few years. HRT was frequently given to women at the time of menopause and continued indefinitely because HRT was considered of clinical benefit to women by ameliorating vasomotor symptoms (hot flashes), improving lipids, and decreasing risk of cardiovascular disease, osteoporosis, and dementia.
How does pregnancy affect thyroid disease?
Pregnant women with hypothyroidism treated with thyroid hormone require approximately 30–50% more thyroid hormone than they did before pregnancy. Initially, thyroid hormone doses are increased by 30% at the time pregnancy test is positive. The thyroid hormone dose increase can by calculated by multiplying the current dose by 1.3 or by adding two extra pills per week. The dose would not be changed for women on thyroid hormone suppression therapy for thyroid cancer or who are already taking excessive thyroid hormone. Thyroid hormone levels should be measured at the diagnosis of pregnancy and every 4–6 weeks during pregnancy. Women can restart their prepregnancy dose the day of delivery.
How does one manage pregnant patients previously treated for Graves' disease?
TSIs and TRAbs should be monitored in the second trimester for patients who have been treated for Graves' disease and are now hypothyroid or euthyroid. If TSIs or TRAbs are positive, fetal Graves' disease may develop. Fetal thyroid ultrasound should be monitored for possible fetal goiter, which can contribute to respiratory distress at birth.