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Disorders of sexual development and sex hormones: Pathology review

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Disorders of sexual development and sex hormones: Pathology review

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Questions

USMLE® Step 1 style questions USMLE

9 questions
Preview

A 16-year-old boy presents to his family physician accompanied by his parents. The patient’s parents are concerned about the patient’s behavior. Over the past six months, the patient has been repeatedly arguing with his parents and performing poorly in school. The patient regularly gets into fights, resulting in several suspensions. Six months ago, the patient did not make the varsity football team, as he usually had every year prior. The patient states, “All I need from you is acne medication, not lessons in how to live my life!” The patient refuses assessment of his vitals. On initial physical assessment, the patient has severe acne, is extremely muscular, and has evidence of male pattern baldness. Which of the following best describes this patient’s expected laboratory findings?  

Transcript

Content Reviewers:

Antonella Melani, MD

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