CTS: Infertility & Delayed Puberty

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Case 1 Infertility
A 27 year old female presents with a three year history of primary infertility. Her cycles are
approximately 28 days, with moderate cramping for the first 1-2 days of menses. Physical exam
is normal and there is no significant past medical history. Her 21 day progesterone level was
normal for the secretory phase of the menstrual cycle. Home LH monitoring reveals consistent
day 12 LH surge. They have had six months of timed-intercourse without pregnancy. After
some difficulty, her husband agrees to be examined. He is 35 years old, has a BMI of 32, smokes
20 cigarettes per day and takes an anti-hypertensive every day. He works on an oil rig and
comes home 2 weeks every 2 months. Physical examination shows a moderate-sized left
varicocele. Semen Analysis shows: Concentration: 1.2 X 10
6
sperm/ml (Normal > 20 X 10
6
), 3.2
X 10
6
total sperm (Normal >60 X 10
6
)
Motility: 49% motility, 20% progressive motility (Normal >45%)
Morphology = 17% normal morphology (Normal >30%)
Upon questioning, the patient admits he did not abstain prior to the sperm analysis. The test is
repeated after three days of abstinence, but the result is unchanged.

Questions

1. What is primary infertility? How common is it? What are the main causes?
Failure to conceive after 12 months of regular unprotected intercourse
10-15% of reproductive age couples
Primary infertility no prior pregnancy
Secondary h/o previous conception
Some conditions (azoospermia, endometriosis, tubal occlusion) are more common in primary infertility,
but all conditions can occur in both settings.
Conception is a highly complex process that requires the interaction and integrity of the female and male
reproductive tracts, which involves
(1) the release of a normal preovulatory oocyte,
(2) the production of adequate spermatozoa,
(3) the normal transport of the gametes to the ampullary portion of the fallopian tube (where
fertilization occurs), and
(4) the subsequent transport of the cleaving embryo into the endometrial cavity for implantation and
development.

- a range of fertility from high to relative to absolute sterility
- top 5 : endometriosis, abnormal sperm count/motility, PCOS, varicocoelse,, PID



2. Why should both partners of the infertile couple be investigated and managed
together?

Infertility is caused by male and/or female factors. Male and female factors each account for
approximately 35% of cases. Often, there is more than one factor, with male and female factors
combined causing 20% of infertility. In the remaining 10% of cases, the etiology is unknown.
In sexual history you should enquire about frequency and method of coitus and knowledge of the
menstrual cycle

3. Assuming the female partner is not ovulating, explain the underlying causes in
physiologic terms? What tests would help you determine the underlying cause?

Oogenesis occurs in the ovary from the first trimester of embryonic life and is
completed by 28-30 weeks of gestation.
By then, approximately 7 million oocytes are present. They are arrested at the prophase
stage of the first meiosis division.
Subsequently, the number of oocytes decreases because of a continuous process of
atresia. At birth, the pool of oocytes is reduced
By menarche, approximately 500,000 oocytes are present. Those oocytes are
used throughout the reproductive years until menopause
The ovulatory process is initiated once the hypothalamus-pituitary-ovarian axis
matures and follicle-stimulating hormone (FSH) and luteinizing hormone (LH),
under the regulation of gonadotropin-releasing hormone (GnRH), acquire their
normal secretory patterns.
From the cohort of follicles available each month, only a single oocyte is
selected, establishes dominance, and develops to the preovulatory stage.
During follicular development, the granulosa cells secrete increasing
amounts of estradiol (E
2
).
through a positive feedback mechanism, E
2
generates the LH surge that triggers
the ovulatory process, induces the resumption of meiosis by the oocyte, and
stimulates the formation of the corpus luteum and subsequent
progesterone secretion.
Ovulatory dysfunction is defined as an alteration in the frequency and duration of the
menstrual cycle. A normal menstrual cycle lasts 25-35 days, with an average of 28 days.
Failure to ovulate is the most common infertility problem. Absence of ovulation can
be associated with primary amenorrhea, secondary amenorrhea, or oligomenorrhea.
Primary amenorrhoea hypogonadotrophic OR hypergonadotrophic or structural
Secondary amenorrhea is the absence of menses for more than 6 months in a woman who has
previously menstruated. Pregnancy should always be ruled out first. In the absence of
pregnancy, this condition is related to dysfunction of the endocrine system and can be
related to thyroid, adrenal, and pituitary disorders, including tumors. One common cause of
secondary amenorrhea is premature ovarian failure, which is the loss of ovarian function by
the age of 40.
Oligomenorrhea is a dysfunction of the hypothalamus-pituitary-ovarian axis and
is the most common ovulatory disorder associated with infertility. Patients
with this disorder present with a history of irregular menstrual cycles that
fluctuate from 35 days to 2-5 months, sometimes associated with a history of
dysfunctional uterine bleeding or prolonged periods of breakthrough bleeding.
Patients may have symptoms of hyperandrogenism, acne, hirsutism, and
baldness. Obesity is frequently associated and aggravates the prognosis.
Although these patients are not sterile, their fertility is decreased, and the
obstetrical outcome is poor because of an increased risk of pregnancy loss. Many
of these women have polycystic ovarian syndrome.
In PCOS cysts are atretic follicles, It is a hyperandrogenic state
Tests: hormone profile FSH, LH, TFT, PL, US, AS,, FBG, lipid profile , 2hr OGTT


4. Explain in physiological terms how hyperprolactinemia may cause anovulation.
See prolactin file

5. Assuming she is not ovulating, how would measurement of serum FSH and oestradiol on
either day 2, 3 or 4 of the cycle assist in the management?

Ovulation is usually inferred when a woman reports regular cycles
(22-35 days), particularly if accompanied by breast changes, bloating
or mood changes.
If there is doubt, a progesterone greater than 4 ng/mL is indicative of
ovulation. Sonographic confirmation of follicle rupture with serial
ultrasonography can also be performed
The level of ovarian reserve and the age of the female partner are the
most important prognostic factors in the fertility workup.
Ovarian reserve is most commonly evaluated by checking a cycle day
3 FSH and estradiol level. Normal ovarian function is indicated when
the FSH level is less than 10 mIU/mL and the estradiol level is less
than 65 pg/mL.
A HIGH FSH indicates a low ovarian reserve. E2 is produced by
granulosa cells in response to FSH. Day 2 -3 because at that time, E2
should be at its lowest and FSH at its highest possible.

6. Assuming she is not ovulating, what drugs could be used to stimulate ovulation and how
do they work?
Clomiphene is a SERM, it acts on estrogen receptors in the hypothalamus to
inhibit the negative feedback of estrogen on gonadotrophin release.
It therefore upregulates the hypothal-pit-gonadal axis
Human menopausal Gonadotrophins: FSH and LH are present in urine of
menopausal women. Also synthethic GnRH.


7. Assuming that she is ovulating, what other test would be indicated and why?
Exlcude uterine, tubal and cervical factors
HSG to demonstrate anatomy of uterus and tube patency, any fibroids
US for polyps, cysts, adenexal masses , fibroids
Laparoscopy for endometriosis, etc

8. What is a varicocoele? Is it surgically correctable?

9. What is the relevance of the lifestyle of the male partner?
Cigarette and marijuana smoking lead to a decrease in sperm density, motility, and morphology.
Alcohol produces both an acute and a chronic decrease in testosterone secretion.
Emotional stress blunts GnRH release, leading to hypogonadism.
Excessive heat exposure from saunas, hot tubs, or the work environment may cause a temporary
decrease in sperm production.


10. What other questions would you ask to exclude other relevant causes of oligospermia?

The initial step in the evaluation of an infertile male is to obtain a thorough medical and urologic history.
Such a history should include consideration of the following:
Duration of infertility
Previous fertility in the patient and the partner
Timing of puberty (early, normal, or delayed) PP or DP indicate endocrine disease
Childhood urologic disorders or surgical procedures - hypospadias/cryptorchidism/ the vas deferens
or the testicular blood supply may be injured or ligated at the time of inguinal surgery, hernia
repair, hydrocelectomy, or varicocelectomy.
Testicular torsion and trauma may result in testicular atrophy

Current or recent acute or chronic medical illnesses - DM produces an auto neurpathy and impotence,
obesity alters hormone balance, liver disese results in inc estrogens and loss of male SSC
Sexual history
the frequency, timing, and methods of coitus and knowledge of the ovulatory cycle should be
elicited.
Studies show that the optimal timing for intercourse is every 48 hours at mid cycle.
Lubricants such as Surgilube, Keri lotion, KY Jelly, and saliva are spermatotoxic,

Testicular cancer and its treatment lead to impaired spermatogenic function, chemotherapy and RT
have dose-dependent effects on germ cells
Social history (eg, smoking and alcohol use)
Medications Spironolactone, cyproterone, ketoconazole, and cimetidine have antiandrogenic properties.

Family history cryptorchidism, hypogonadotropism, and testicular atrophy in family members may be a
sign of a congenital disease.
A history of CF or hypogonadism should be elicited.
Respiratory disease
Infertility and recurrent respiratory infections may be due to immotile cilia syndrome (PCD), which
may be isolated or part of Kartagener syndrome (with situs inversus).
CF is associated with congenital bilateral absence of the vas deferens (CBAVD), leading to
obstructive azoospermia. While both copies of this recessive gene are necessary for clinical
disease, the presence of only one copy may lead to CBAVD.
Environmental or occupational exposure
Spinal cord injury - anejaculation



11. What determines the volume of the testes and how is this assessed?

Volume of the testes is an indicator of testicular development, function and
spermatogenesis. Testicular size is determined by pubertal development and therefore
it depends on GnRH, FSH, LH and testosterone. Seminiferous tubules comprise 80-90%
of testicular mass. Thus, the testicular volume is believed to be an index of
spermatogenesis. Small testes represent primary or secondary hypogonadism.

Testicular size is measured using a Prader orchidimeter. It consists of a string of twelve
numbered wooden or plastic beads of increasing size from about 1 to 25ml. Prepubertal
sizes are 13 ml, pubertal sizes are considered 4 ml and up and adult sizes are 1225 ml.


12. Assuming the sperm count had shown severe oligozoospermia (< 5 million sperm) or
azoospermia, what investigations might be indicated?

The semen analysis is the cornerstone of the male infertility workup. A specimen is collected by
masturbation into a clean, dry, sterile container or during coitus using special condoms (containing no
spermicidal lubricants).
The patient should be abstinent for 2-3 days prior to maximize sperm number and quality. Each day of
abstinence is typically associated with an increase in semen volume of 0.4 mL and an increase in sperm
density by 10-15 million sperm/mL, for up to 7 days. The sample should be processed within 1 hour, and
2-3 samples (at a minimum of 2-3 days apart) should be evaluated because of daily variations in sperm
number and quality.
Various parameters are measured, such as ejaculate volume and sperm density, quality, motility, and
morphology.
Hormonal analysis
Fewer than 3% of cases of male infertility are estimated to be due primarily to a hormonal cause.
A routine part of the initial evaluation is testing of specific serum hormone levels, which usually includes
FSH, LH, testosterone, and prolactin.
Abnormalities may be a sign of a primary hypothalamic, pituitary, or testicular problem.
Other tests include testicular US, TRUS, biopsy, post coital tests

13. What is the most common congenital abnormality resulting in testicular dysfunction?

The most common congenital abnormality resulting in testicular dysfunction is
cryptorchidism. The longer the testis remains outside the scrotum, the greater the degree of
spermatic disruption. This effects 3% of full terms and 30% of preterm boys, most however
correct spontaneously within the first 3 months of life.

The undescended testes can be located anywhere along the path of descent from
retroperitoneum to inguinal canal, it can be ectopic [outside this path] or severely dysplastic.

Undescended testes are associated with reduced fertility, increased risk of testicular germ cell
tumors. Many men who were born with undescended testes have reduced fertility, even
after orchiopexy in infancy. At least one contributing mechanism for reduced
spermatogenesis in cryptorchid testes is temperature. The temperature of testes in the
scrotum is at least a couple of degrees cooler than in the abdomen.

14. What is the most common chromosomal abnormality resulting in deficient testicular
function?

The most common chromosomal abnormality resulting in deficient testicular function is
Klinefelter's syndrome. This is 47 XXY, commonly due to nondisjunction of X and Y in the
first meiotic prophase and is second to Downs syndrome in terms of prevalence.
A sperm with both X and Y is produced which then fertilizes and X oocyte to produce XXy
karyotpe

XXY males have hypogonadism with small testes and gynecomastia

XXY males are usually tall but no dysporphology. Males have microorchidism, subfertility,
some gynecomastia, low serum testosterone but high FSH and LH.
Some learning disabily and speech problems might be present.

15. Why was it necessary to repeat the sperm analysis after abstinence? What other factors
might interfere with the test result?

16. What is Intracytoplasmic Sperm Injection?

ICSI is an IVF technique where a single sperm is directly injected into an oocyte. Used in male
fertility issues

17. What other Assisted Reproductive Techniques are available and how do they differ?

18. How many infertile couples eventually conceive?

4 couples out of every 10 treated for infertility deliver a healthy baby
but success depends on cause, e.g. low for azospermia, high (90%) for amenorrhoea

Case 2 Delayed Puberty
The worried parents of a 16 year old girl who has no breast development and no periods take
their daughter to their family doctor for advice and reassurance. Her BMI is 16 and she is
training 20 hours per week for the Mediterranean Games (Gymnastics).

1. What is puberty?
A developmental process that culminates in sexual maturity
Begins in late childhood (age10-16) and involves
o Maturation of H-P-Gonadal axis
o Appearance of SSC
o Acceleration of growth
o Acquisition of fertility
o Accompanied by physical, endocrine and psychological changes
Begins age 8-13 in girls, 9-14 in boys

2. Puberty may be said to be the coordinated consequences of adrenarche and
gonadarche. Explain why.

Androgen production by the ZR of the adrenal cortex is the initial endocrine
change of puberty
In late prepuberty rise of AS, DHEA-S, DHEA independent of
gonadotrophins
These produce growth of axillary and pubic hair adrenarche
Gonadarche: the initiation of production of significant amount of sex steroids
by the testis or the ovary related to stimulation by gonadotropins
Adrenarche occurs usually one to two years before gonadarche
and is independent of gonadarche. Children without functioning
gonads will achieve adrenarche.

3. Explain why the stage for puberty is set during fetal life.

The foetal HPG axis is capable of producing adult levels of FSH, LH, and sex steroids.
It remains suppressed pre puberty due to
- increased sensitivity to negative feedback effect of sex hormones present in very
low levels
- intrinsic inhibition of GnRH release by CNS

Puberty involves the loss of feedback inhibition of GnRH and GnRH pulses increase,
leading to FSH and LH release

4. Explain in physiological terms how puberty can be artificially initiated in children
without functioning gonads (Turner's Syndrome, XO gonadal dysgenesis).

Low dose estrogen and testosterone supplements in female s and males

5. Explain in physiological terms why gonadotrophin-secreting pituitary tumours may be
associated with precocious puberty (< 8 years in girls, < 9 years in boys).

PP can be gonadotrophin dependent (High FSH, high LH) rare. Central PP in males is usually
organic e.g. intracranial tumours that secrete GnRH.
PP is trigerred by gonadotrophins as before normal puberty, the Hypothalmic-Pituitary-Gonadal
axis is suppressed. This suppression is due to
a) increased sensitivity to negative feedback effect of low sex hormone levels present
in the circulation
b) intrinsic inhibition by CNS of GnRH release
Normal puberty is triggered by the pulsatile increase in GnRH levels that promotes FSH, LH and
sex steroid production


6. What is the first sign of puberty in females?

a. Breast development (thelarche)
b. Pubic hair growth and rapid growth spurt
c. Menarche usually 2 years after start of puberty signals end of growth

7. What is the first sign of puberty in males?
a. Testicular enlargement (>4ml on orchidimter)
b. Pubic hair growth
c. Height spurt when testicular volume is 12-15ml

Male height spurt is later and greater than females
In both involves GH, IGF1 and gonadal steroids
Staged clinically into 5 stages Marshall and Tanner
Post puberty, girls have less skeletal and lean body mass and greater % of body fat


8. What is the likeliest cause of delayed puberty in this case? What are some of the other
causes?


Delayed puberty is common in males
Commonest cause is constitionial delay often a documented FH of DP exists. In such
cases, normal puberty occurs and children attain their predicted height.

In this case XS exercise can suppress gonadotrophin levels. Same process occurs in
severe systemic disease e.g. cystic fibrosis, anorexia, extreme weight loss.

Delayed puberty can also occur due to panhypopitutarism, GH deficiency, Kallmann
syndrome, hypothyroidism.

Hypergonadotrophic hypogonadism causes absent/delayed puberty with high FSH e.g.
Turner, Klinefelters, etc.