MCW COOP 2009

Development 112205 11:00

Reproductive Case Study
Dr. James Aiman
Writer: Drew Hietpas

For all of you that don’t remember who Dr. Aiman is, he is the very entertaining OB/GYN who gave us the
infertility lecture earlier this semester. He took virtually the same approach in that lecture as he did in this
one. By that I mean he instructed us not to take notes, but to simply sit back and listen. He also provided us
with a copy of his exam questions and answers (attached to the back page) so I guess I can’t blame you if
this is the last paragraph of the COOP that you read.
Dr. Aiman began the lecture stating that he did not want us to take notes because he was going to reinforce
most of the things that Dr. Bolender mentioned in his lecture. The purpose of his lecture was to illustrate
how a clinician uses the basic sciences to diagnose and treat patients with genital ambiguity. The notes for
this lecture are included with the rest of our development notes.

Sequential events in male sexual differentiation

1. Mullerian duct regression 32mm* (56 days)
2. Leydig cell appearance 35 mm (58 days)
3. Testosterone secretion 40 mm (61 days)
4. Virrilization complete 190 mm (140 days)
*crown-rump length (gestational age)
Gestational age -age used by clinicians beginning at the date of last menstruation
Fertilization age- age used by embryologists beginning at the date of conception
Typically there is a two week difference Gestational and Fertilization ages.

The major clinical events that occur in sex differentiation

1. Mullerian duct regression
2. Testosterone synthesis
3. Conversion of testosterone to dihydrotestosterone (responsible for differentiation of the male
external genitalia)

Genital Ambiguity means abnormal testosterone representation in utero, that occurs in the first 3-4 months
of development. Abnormal testosterone levels are a result of:
• Too much testosterone produced
• Too little testosterone produced
• Abnormality of testosterone receptors
The first question that clinicians must address when treating a patient with ambiguous genitalia is: Is this
child genetically supposed to be a male or a female?

Definition of a male: has Y chromosome, no uterus, and having testes.

Definition of a female: no Y chromosome, a uterus, and no testes.
**notice that the definition of a female does not involve presence of ovaries or X chromosomes**

Possible conditions of patients with ambiguous genitalia

Male Pseudohermaphrodite- a person with ambiguous genitalia who is genetically male
Female Pseudohermaphrodite-a person with ambiguous genitalia who is genetically female.
True Hermaphrodite- both ovarian and testicular tissue are present in the same individual.
**It is important to acknowledge that nothing about the external genitalia of these patients will help to
determine which of these conditions a patient may have.**

True Hermaphrodite
To illustrate what occurs in the case of a true hermaphrodite, Dr. Aiman showed a slide of a resected gonad
from one of these patients. The gonad cut in half and two distinct regions/tissue types were visible. The
darker, more condensed tissue of the gonad was testicular tissue, and the lighter less condensed tissue was
ovarian tissue. Next he showed a slide of a gonadal tissue sample, and pointed out the seminiferous tubules
and ovarian follicles present in the same gonad. When both tissues are found in the same gonad the gonad
is referred to as a ovotestis.

Diagnosis of Male Psuedohermaphrodite: See the flow chart on page 4.

This condition is caused by either too little testosterone production or abnormal testosterone receptors. As a
result a clinician must measure the patients testosterone levels.
Low levels of testosterone indicate that the child is not producing enough testosterone.
High levels of testosterone indicate that the child has androgen resistance.

If the child has a deficiency in testosterone synthesis the next step is to test for the concentration of
testosterone precursors.
Low levels of testosterone precursors indicates absent testes or leydig cells.
High levels of testosterone precursors indicates a steroid enzyme defect.

Next Dr. Aiman, took about a minute to explain to us the steroid biosynthetic pathways and provided us
with the diagram on page 6 (it should look familiar). He explained to us that it is not necessary to
memorize these pathway because the clinicians themselves do not memorize them. Too bad he’s not
teaching Block 3 biochem, hey? However, to determine the defective enzymes in the steroid pathway it is
necessary to review the steroid biosynthetic pathways.

Diagnosis of Female Pseudohermaphrodites. See the flow chart on page 4.

Remember the definition of a female- no Y chromosome, uterus present, and no testes.

This condition is caused by excess testosterone production in a genetically female patient.
We must first determine whether the cause of excess testosterone production is a result of production by the
mother or the fetus.

Sources of excess testosterone production

Maternal: Child:
medications activity of adrenal glands
activity of the adrenal glands activity of ovaries
activity of the ovaries.

The rest of the class period was dedicated to the case studies presented on pages 7-9.

Case A. A 17 year old female consults you because she has never menstruated. She has no breast growth
and infantile-appearing female genitalia. The concentrations of estradiaol and testosterone are very low.
She has no affected family member. She has no uterus. A karyotype was obtained and a laparotomy was
performed.

1. Which sex is expressed in this woman?

Neither sex steroid is expressed, this is a characteristic of infantile-appearing genetalia. Both
testosterone and estradiol levels are low. There is no breast growth to indicate estrogen production. More
importantly the absence of male external genetalia indicates an absence of testosterone/
dihydrotestosterone.

2. What is her karyotype?

46XY. The patient is genetically male because she does not have a uterus.

3. What is your differential diagnosis?

The patient is Male pseudohermaphrodite. We were told that the patient is not androgen resistant
and her level of steroid precursors are low. Therefore, this patient either has absence of the testes or leydig
cells. The laparotomy was performed and no gonads were present. As a result our final diagnosis is
absence of the testicles or anorchism.

4. What is your treatment?

This question has some ethical issues involved. Although this patient is genetically male, she has
been raised as a female for 17 years, therefore, we shall consider her a female. Dr. Aiman stated that it is
unethical to attempt to reassign a gender after the age of two. Also it is important to note that this patient
had infantile genitalia and not ambiguous genitalia so it is not necessary or beneficial to attempt to reassign
sex since there is no sign of male genitalia. The treatment is this case would be estrogen replacement
therapy.

Dr. Aiman also mentioned a condition called vanishing testis syndrome. In this condition the testes
do form but eventually atrophy. If the testes disappear before the testosterone production phase of
development, infantile genitalia will be present. If the testes disappear later there will be varying degrees
of masculinization of genitalia.

Case B. A 21 year old woman presents with primary amenorrhea, adequate breast development, absent
pubic and axillary hair, and no uterus. Affected family members are present only on the maternal side. Her
serum testosterone concentration is 780 mg/dl [normal: <110 (female), 200-1000 (male)]

1. What is her karyotype?

46 XY, no uterus indicates that she is genetically male.
2. Does she have ovaries or testes?
She has testes.
3. What is the pattern of inheritance?
The pattern of inheritance is X-linked recessive. The condition is was present on the maternal side
of the family, and she inherited the disorder as genetic male. This is typical X-linked recessive inheritance.
4. Should we remove her gonads?
Yes, because undescended testicles are often found to be carcinogenic.
5. What is your diagnosis?
The diagnosis is an androgen receptor abnormality because her testosterone levels were
considered within the normal range for a male.
6. What is your treatment?
She is a female, therefore we will treat her with estrogen replacement.
7. What do you tell the patient and her family?
Another ethical question, but Dr. Aiman chose not to answer. He stated that we must always
remember to do what is in the best interests of our patient.

Case C. A 16 year old girl and her parents consult you because she had ambiguous genitalia at birth,
progressive phallic enlargement during childhood, early puberty (age 8), short stature, and primary
amenorrhea. Early n puberty she grew rapidly and was taller than her peers. However, growth cease by
age 11-12 years and her peers are now taller. Her blood pressure is normal. She is obviously masculinized
and has both marked phallic enlargement and posterior labial fusion. A uterus is palpable. Cortisol
concentrations are low but progesterone and 17-OH Progesterone are high.

1. What is her karyotype?

46XX, she has a uterus.
2. Does she have ovaries or testes?
Ovaries
3. Is her plasma ACTH concentration low, normal, or high?
High, she is not producing cortisol, therefore there is no negative feedback mechanism to the
anterior pituitary to tell it to stop producing ACTH.
4. What is your diagnosis?
21 Hydroxylase deficiency. See Diagram on pg 6. Lack of coritsol and a high concentration of the
precursors progesterone and 17 OH progesterone indicate a defect in 21 hydroxlase enzyme.
5. What is treatment?
 We would treat with Cortisol, to decrease ACTH levels. Decreased ACTH will decrease the
androgen precursors and therefore reduce synthesis of androgens.
6. Will she menstruate and conceive with treatment?
Yes
Case D. You see a 15 year old girl with primary amenorrhea and hypertension. You also see her 17 year
old sister who also has primary amenorrhea and hypertension. The 15 year old has a uterus but the 17 year
old does not . Both are sexually infantile (no breast development, absent to scant pubic hair.
1. What is the diagnosis of the 15 year old?
17 alpha hydroxlase deficiency. The presence of a hypertension indicates excess mineralcorticoid
synthesis. The infantile genitalia demonstrates that there are no sex hormones being produced (As in Case
A).
2. What is the diagnosis of the 17 year old?
She has the same deficiency 17 alpha hydroxlase deficiency, however, she is genetically male due
to absence of a uterus. Therefore she is a male pseudohermaphrodite due to the lack of sex hormone
production. (Remember, when no sex hormones are present, female external genitalia is the default). No
testosterone=> no dihydroxytestosterone => no male external genitalia.

3. Are their plasma ACTH levels low, high, or normal?

High, because there is a low cortisol production.
4. Are their serum FSH and LH concentrations low, normal, or high?
High, there are no sex hormones produced, therefore no negative feedback to the anterior pituitary
to stop secreting FSH and LH.
5. What is the pattern of inheritance?
******If there is one thing from this lecture you should try to remember for you OB rotation it is
the answer to this question***** All deficiencies in the steroid biosynthetic pathway are autosomal
recessive. Don’t be fooled into thinking sex-linked inheritance due to the fact that two sisters have the
same disease, because actually one of the sisters is a genetic male.
6. What is the treatment?
Cortisol and Estrogen for both.

Case E: You are asked to see a newborn infant with partially fused labioscrotal folds and a phallus tooo
large to be a clitoris. A uterusis palpable on rectal examination. There is no one in 3 generations with a
similar problem. Serum electrolytes are normal, as is the infants 17OH progesterone concentration. A
karyotype is 46, XX.

1. What one important question as ded of the mother was omitted from the history. What was that
question?
Are you on any medications?

2. Virilization of a female means too much or toolittle of what steroid(s)?

Too much androgens
3. What is your diagnosis?
We were told that the mother was taking danizol, a weak androgen, used in the treatment of
endometriosis. This drug suppresses the ovaries and renders amenorrhea. She had begun treatment with
danizol after she had unknowingly conceived her child. She had been taking the danizol for a seven months
and did not notice that she was pregnant because danizol is designed to produce amenorrhea. Our diagnosis
is that the danizol in the mother’s system resulted in the increase in the androgen/testosterone levels
exposed to the fetus. The danizol caused the baby to have ambiguous genitalia.
4. What is the treatment what is the treatment and when do you treat?
The treatment is an operation to give female genitalia (in Dr. Aiman’s opinion it’s easier to dig a
well than to build a derrick). No other treatment is necessary because the mother was the source of excess
testosterone production. Dr. Aiman did not mention when the surgery is to be performed, however, I
believe on of his slides (which were not online when I wrote this) it mentioned that the surgery was to be
performed either before or after puberty.