Disorders of sexual development and sex hormones: Pathology review

Clay, a 17 year old male arrives at the clinic after noticing that he’s not developing like his friends. On further questioning, Clay mentions that he was born without a sense of smell. Upon physical examination, you notice that he has no facial or body hair, and that his external genitals are small and underdeveloped for his age. You decide to run a blood test, which shows low levels of the hormones GnRH, LH, FSH, and testosterone. Finally, you order a semen analysis, which reveals a low sperm count.

Next comes Jessie, a 13 year old girl, and her concerned mother, who’s noticed that Jessie has started to develop some masculine features, such as a deeper voice and excess body hair growth. A blood test shows increased testosterone levels and low dihydrotestosterone, so you decide to perform a karyotype test, which reveals 46 chromosomes, with one X and one Y chromosome.

Okay, now based on their initial presentation, both Clay and Jessie seem to have some form of disorder of sexual development and sex hormones.

But first, let’s go over some terminology! On the one hand, we all have a genotypic sex, which is determined by our karyotype or set of chromosomes. Generally, there are two sex chromosomes; those who have X and Y sex chromosomes are typically considered genetically males, while those who only have X chromosomes are typically considered genetically females. On the other hand, phenotypic sex is determined by the primary sexual characteristics, so the genitalia and gonads, as well as the secondary sexual characteristics, such as breast and muscle development, as well as body hair and fat distribution.

The development of primary and secondary sexual characteristics is generally under control of the hypothalamic-pituitary-gonadal axis. First, the hypothalamus secretes gonadotropin-releasing hormone, or GnRH for short, which goes to the anterior pituitary to stimulate the release of gonadotropic hormones, which are luteinizing hormone or LH, and follicle-stimulating hormone or FSH. LH and FSH then stimulate the gonads to produce sex hormones; in males, LH stimulates the Leydig cells of the testes to secrete testosterone, and FSH stimulates the Sertoli cells to secrete inhibin B. Testosterone and inhibin B are responsible for the development of male primary sexual characteristics, like enlargement of the penis and testes; as well as male secondary sexual characteristics, such as a deepening of the voice, a male pattern of hair growth on the face, chest, axillae, and genital areas, and increased muscle mass.

On the other hand, in females, LH and FSH stimulate the ovaries to secrete estrogen and progesterone, which are responsible for the female primary sexual characteristics like ovulation, menstruation, and uterine development; as well as female secondary sex characteristics like breast development, hip widening, and hair growth mainly on the axillae and genital areas. Now, once sex hormones have done their job, they signal the hypothalamus and pituitary via negative feedback to turn off the secretion of GnRH, LH, and FSH.

Now, disorders of sexual development, or DSD for short, are characterized by a discrepancy between an individual’s genotypic and phenotypic sex. Let’s say there’s an individual that has a 46,XY karyotype, so they’re genetically male and they have testes, but their external genitalia show a feminine or ambiguous appearance. So this is called a 46,XY DSD. The opposite scenario would be an individual with a 46,XX karyotype, so they’re genetically female and have ovaries, but present with virilized or ambiguous external genitalia. And this is called a 46,XX DSD. The previous terminology for DSDs includes terms like hermaphrodite or pseudohermaphrodite. However, these terms can be considered derogatory, so they’re no longer in common use. And although currently the most widely used term is disorders of sexual development, keep in mind that it’s also falling out of favor, since it’s considered overbroad, and the word ‘disorder’ may have a negative connotation. So, don’t be surprised if there’s a new term in the future!

For your exams, some high yield disorders of sexual development and sex hormones include ovotesticular disorder, androgen insensitivity syndrome, 5ɑ-reductase deficiency, placental aromatase deficiency, Kallmann syndrome, precocious puberty, and androgenic steroid abuse.

Let’s start with ovotesticular disorder. Now, the cause of this disorder isn’t totally clear. What’s important for your exams is that most individuals with ovotesticular disorder have a 46, XX karyotype, so they’re genetically female. But keep in mind that it can also affect individuals that are 46,XY, as well as those who have a mosaic karyotype where some cells are 46,XX, while others are 46,XY! Now, as the name suggests, individuals with ovotesticular disorder have a mixed phenotypic sex. Most affected individuals present with ovotestis, which is a gonad made up of a combination of ovarian and testicular tissue. On the other hand, some affected individuals may develop an ovary on one side, and testis on the other. In addition, individuals with ovotesticular disorder usually have ambiguous genitalia, meaning that the appearance of their external genitalia isn’t clearly male or female. Previously, ovotesticular disorder was called true hermaphroditism after the Greek god Hermaphroditus, who was united with the nymph who fell in love with him into a single body with both masculine and feminine characteristics. Nowadays, this term is no longer used.

Next we have androgen insensitivity syndrome, which is the most common form of 46,XY DSD. This is caused by a mutation in the androgen receptor gene, which is found on the X chromosome. Androgen insensitivity syndrome is an X-linked recessive disorder, so it typically affects genetic males, because they have only one X chromosome. On the other hand, genetic females generally have two X chromosomes, so even if they have a defective gene on one chromosome, they still have another functional one.

Okay, normally, during the first trimester of fetal life, the gonadal sex develops either into testes or ovaries. In males, a gene on the Y chromosome called the sex-determining region Y or SRY gene, helps the fetal gonads turn into testes, which are initially located in the abdomen. In turn, the testes start producing androgens, the main one being testosterone. A small fraction of testosterone gets converted by the enzyme 5α-reductase into its more potent form, called dihydrotestosterone or DHT, which is mostly responsible for development of male external genitalia. And that’s a high yield fact! Internally, there’s a set of ducts, called Wolffian and Mullerian ducts. Testosterone also causes the Wolffian ducts to differentiate into the male reproductive system. At the same time, the testes also produce a hormone called anti-Müllerian hormone, which prevents the Müllerian ducts from developing into the female reproductive system, and instead makes them degenerate. During the third trimester, testosterone helps the testes descend from the abdomen into the scrotum. On the other hand, in females, there’s no Y chromosome so the SRY gene is absent. As a result, ovaries develop from the internal gonads, and androgen levels remain relatively low, so they develop female external genitalia.

Now, individuals with androgen insensitivity syndrome have normal functioning testes that produce androgens, but these hormones can’t exert their action, because there’s a defect in the androgen receptor. Without the effects of androgens, the testes sometimes don’t descend into the scrotum, and instead remain in the abdomen or pelvis, which is called cryptorchidism. What’s important for your exams is that cryptorchidism is related to a higher chance of developing testicular cancer later in life. Additionally, with androgen insensitivity syndrome, the genitals develop an overall feminine appearance, with a rudimentary vaginal opening, and a normal-looking clitoris and labia. Even though androgen influence is missing, the testes still produce anti-Müllerian hormone, which means that these individuals don’t have a uterus and fallopian tubes, and thus their vagina ends in blind pouch.

During puberty, some of the excess androgens may end up being converted to estrogen by the enzyme aromatase. As a result, affected individuals may develop female secondary sex characteristics, such as widening of the hips, gynecomastia or breast growth, and scant pubic and axillary hair.

Androgen insensitivity syndrome can sometimes remain undiagnosed until puberty, when an individual that has female genitalia doesn’t start menstruation. And on a blood test, individuals with androgen insensitivity syndrome may have increased levels of testosterone, estrogen, and LH. Finally, a karyotype test can be done to confirm the genotypic sex.

Treatment typically involves surgical removal of the testes, especially in the case of cryptorchidism, to reduce the risk for cancer. In addition, individuals who choose to adopt a female gender identity can use estrogen supplements, while those who adopt a male gender identity can use testosterone or DHT supplements.

Another high yield 46,XY DSD fact is 5ɑ-reductase deficiency, which is caused by a mutation in the SRD5A2 gene. What you need to know is that this gene codes for the enzyme 5ɑ-reductase, which normally converts testosterone to DHT. For your exams, remember that 5ɑ-reductase deficiency is inherited in an autosomal recessive but sex-limited pattern. This means that for the disease to appear, both copies of the gene have to be mutated and the individual has to be genetically male, since dihydrotestosterone has no role in female sexual development. And that’s very high yield!

With 5ɑ-reductase deficiency, the problem arises in a male fetus where the testes produce testosterone, but it isn’t converted to DHT. As a result, they develop male internal sex organs, but the external genitalia appear ambiguous or female. In particular, the penis doesn’t fully elongate, and the scrotum often remains split in two, which is also called a bifid scrotum.

When these individuals reach puberty, there’s a huge testosterone surge. So, even though it can’t be converted to DHT, there’s so much testosterone around that the penis and scrotum grow larger and start acquiring a masculine appearance. In addition, individuals start developing a deeper voice, muscle growth, and facial and body hair growth.

Diagnosis of 5α-reductase deficiency is usually suspected in newborns with ambiguous genitalia, and a karyotype can be performed to confirm the genotypic sex. What’s high yield is that blood tests usually show normal serum testosterone and estrogen levels, low DHT levels, and normal or increased LH levels. Treatment of 5α-reductase deficiency is focused on hormone replacement therapy.

Moving on, placental aromatase deficiency is a 46,XX DSD caused by a mutation in the CYP19A1 gene, which codes for the enzyme aromatase that normally converts androgens to estrogens. Now, placental aromatase deficiency is also inherited in an autosomal recessive but sex-limited pattern, but unlike 5α-reductase deficiency, this mainly affects genetically female individuals, since estrogens are the main female sex hormones. And that’s very high yield!

Now, during gestation of a baby affected with placental aromatase deficiency, the abnormally high androgen levels from the fetus can cross the placenta into the mother’s bloodstream. As a result, there’s maternal virilization, which is characterized by deepening of the voice, hirsutism or excessive body hair growth, and acne or multiple skin pimples mainly involving the face. Keep in mind that maternal virilization usually regresses after giving birth, when the fetal androgens aren’t around anymore.