Endocrine Infertility

1. Endocrine Infertility

2. Hormones in Male Fertility
GnRH
LH
FSH
Testosterone
Prolactin
Inhibin B
Estrogen

3. Introduction
 The hypothalamus–pituitary–testis (HPT)
axis is the most important endocrine system
in the human male.
 HPT axis is the descriptive term for an
integrated mechanism by which the brain
signals the male reproductive system to
carry out its two main functions – androgen
secretion and spermatogenesis.

4. H P T Axis
4

5.  Kisspeptin via its receptor
GPR54 on the GnRH
neurons in hypothalamus
stimulates the release of
GnRH
 GnRH is secreted in a
pulsatile fashion
H P T Axis

6.  GnRH enters the pituitary portal
circulation and reaches the
gonadotroph cells in the
anterior hypophysis, which
release :
◦ Follicle-stimulating hormone
(FSH), and
◦ Luteinizing hormone (LH)
H P T Axis

7.  LH stimulates the testosterone
biosynthesis in the Leydig cells,
while
 FSH supports spermatogenesis
and stimulates the secretion of
both inhibin B and anti-
Müllerian hormone (AMH) by by
the Sertoli cells
H P T Axis

8.  Testosterone via androgen
receptors on Sertoli cells plays
an important role in
spermatogenesis and
decreases the AMH production
 Sertoli cells via production of
inhibin B decrease FSH
secretion.
 Testosterone directly as well as
after aromatization to estradiol
feeds back negatively on the
LH secretion.
H P T Axis

9.  Male infertility is caused by endocrine
alterations in 18–30 % of cases
 Potentially reversible cause of some
cases of male-factor infertility
Endocrine Infertility

10.  Hyperprolactinemia
 Hypogonadotropic Hypogonadism
 Hypergonadotropic Hypogonadism
 Hypogonadism with Normal or
Elevated Testosterone
Endocrine Infertility

11. 1.
HYPERPROLACTINEMIA

12.  May be caused by Prolactin-secreting pituitary
tumor
 Other causes : hypothyroidism, systemic
diseases, stress, and medication, such as :
neuroleptics, tricyclic antidepressants, SSRIs,
verapamil, methyldopa, reserpine, metoclopramide,
domperidone, H2-blockers, opiates, cocaine, estrogens,
and protease inhibitors
 Most common symptoms include : decreased
libido, erectile dysfunction, gynecomastia, and
infertility
 Headache or visual field defects caused by an
enlarging adenoma

13.  Prevalence :
◦ 11% of oligozoospermic men
◦ 16% of men with impaired erectile function
 Is considered to be the most common
endocrinologic cause of hypothalamic– pituitary
axis diseases
 It is characterized by the presence of abnormally
high levels of prolactin
 Resulting depression of LH and FSH secretion
via negative feedback on the hypothalamus.
 Leads to reduced levels of serum testosterone
and impairment of spermatogenesis causing
oligozoospermia and infertility

14. 2.
HYPOGONADOTROPIC
HYPOGONADISM
(SECONDARY HYPOGONADISM)

15.  Hypogonadotropic hypogonadism (HH) is a
state of
◦ low androgen secretion as a result of
◦ absent or low gonadotropic stimulation,
 Which may be either congenital or acquired

16. Failure of Hypothalamus
Congenital Idiopathic Hypogonadotropic
Hypogonadism (IHH) / Kallmann’s Syndrome
 Two types:
◦ Classic Kallmann’s syndrome, with anosmia
◦ Normosmic Kallmann’s syndrome (nIHH)
 Incidence of 1 in 8000 - 10000
 Diagnosed due to lack of pubertal development,
with prepubertal-sized testes and absent
virilization, in concert with low gonadotropins and
steroids, as well as a compromised sense of smell.
 These patients may also have cleft lip or palate,
bimanual synkinesis, renal agenesis, eye
movement abnormalities, congenital ptosis, or
hearing impairment

17.  There is a subset of late onset or acquired IHH
that presents with hypogonadism associated
with inappropriately low gonadotropins and is
accompanied with erectile dysfunction and new
onset infertility
Failure of Hypothalamus
Congenital Idiopathic Hypogonadotropic
Hypogonadism (IHH) / Kallmann’s Syndrome

18. Pituitary Insufficiency
 Incidence: 11.9–42.1 cases per million
inhabitants per year
 Prevalence: 300–455 per million inhabitants.
 Clinical symptoms may be subtle; however, if
the portion of the anterior pituitary that secretes
LH or FSH is involved, HH may result.

19.  The causes of hypopituitarism are varied,
◦ can be of prepubertal or adult onset, and include
perinatal damage,
◦ Tumors, Traumatic brain injury, cerebral irradiation,
◦ Pituitary infarction following severe illness,
lymphocytic hypophysitis, subarachnoid
hemorrhage, infections,
◦ Granulomatous diseases (i.e., neurosarcoid),
◦ Infiltrative disease such as amyloidosis or
histiocytosis X, and
◦ Diseases that cause iron overload which can be
deposited in the pituitary resulting in decreased
gonadotropin
Pituitary Insufficiency

20.  Rare, but reported cause of infertility or
subfertility.
 Men affected with the syndrome have normally
masculinized genitalia at birth secondary to
placental hCG activity;
 however, they typically fail to go through puberty
and therefore exhibit a eunuchoid body habitus
with small testes as adults
 These patients demonstrate low testosterones,
but may have either elevated LH activity or
undetectable LH levels depending on whether or
not the mutant LH protein is immunoreactive
Isolated Luteinizing Hormone Deficiency

21.  A milder phenotype,
 Delayed puberty, and oligoasthenozoospermia but
demonstrating normal gonadotropin levels and
relatively preserved testis size (18 mL).
 a mutation in the LHB subunit produced a variant
LH with lower receptor-binding activity.
 When treated with hCG, the patient virilized
normally with correction in his semen parameters;
however, upon cessation of hCG, his
hypogonadism returned
Isolated Luteinizing Hormone Deficiency

22.  Most, but not all, men displayed oligozoospermia
or azoospermia.
 Most had normal testosterone and normal
pubertal development with testis biopsies varying
from normal to maturation arrest
Isolated Follicle Stimulating Hormone Deficiency

23.  Syndromic genetic disorders including:
◦ Prader–Willi,
◦ Alstrom’s,
◦ familial cerebral ataxia,
◦ and Laurence–Moon–Biedl syndrome
Other Syndromes Leading
to Hypogonadotropic Hypogonadism

24. 3.
HYPERGONADOTROPIC
HYPOGONADISM
(PRIMARY HYPOGONADISM)

25.  Men with hypergonadotropic hypogonadism can be
subdivided into two major groups :
◦ men with classic hypergonadotropic hypogonadism
identifi ed by elevated gonadotropin levels, low
testosterone level, and severe oligospermia or
azoospermia (testicular failure), and
◦ men with spermatogenic failure without Leydig cell
failure, who present with elevated serum FSH levels,
normal LH and testosterone levels, and oligospermia
or azoospermia

26. Primary Testicular Failure
 Primary testicular failure is classified into four
distinct subtypes:
◦ sertoli cell only syndrome (SCOS),
◦ germ cell/maturation arrest (GCA/MA),
◦ hypospermatogenesis (HS) and
◦ tubular fibrosis (TF)
 Histopathology

27. Klinefelter Syndrome
 The most frequent karyotypic
abnormality detected in
infertile men,
 prevalence of 1 in 660,
 It is often undiagnosed
during infancy to early
puberty

28. Klinefelter Syndrome
 The gonadotropin and androgen levels are relatively
normal;
 however, at the onset of puberty, the serum
testosterone concentration plateaus in the low normal
range, an elevation in the estradiol level is seen, and
the FSH and LH levels rise and coincide with decreased
inhibin B levels
 By the time these men reach adulthood, 65–85% have
low serum testosterone concentrations
 In addition, hyalinization of the seminiferous tubules
and Leydig cell hyperplasia are present in adult KS
testes

29. Gonadal Toxicity
 Following treatment with cytotoxic chemotherapy
and radiotherapy, there is a high risk of developing
Leydig cell dysfunction, identified as elevated LH
levels in conjunction with low to normal testosteron

30. Inactivating Luteinizing Hormone Receptor
Mutations
 LH receptor and FSH receptor belong to G-protein-
coupled receptor family
 Androgen synthesis occurred by the stimulation of
the LHR, whereas FSHR activation promotes the
Sertoli cells function and maintains spermatogenesis
 Gonadotropin receptor mutations have been found in
some patients with hypogonadal states and pubertal
abnormalities

31. Inactivating Luteinizing Hormone Receptor
Mutations
 Inactivating LHR mutations present as
hypergonadotropic hypogonadism with
pseudohermaphroditism and histologic evidence
of hypoplastic Leydig cells
 In these cases, Sertoli cell histology and numbers
are not affected

32. Inactivating Follicle Stimulating Hormone
Receptor Mutations
 A mutation in the FSHR results in variable degrees of
spermatogenetic dysfunction causing infertility.
 Patients present with a moderately elevated FSH,
normal or slightly elevated LH, normal testosterone, and
variable reduction in testicular size.
 The semen analysis may demonstrate oligozoospermia;
however, normal spermatogenesis may still be
maintained.

33. 4.
HYPOGONADISM WITH
NORMAL OR ELEVATED
TESTOSTERONE

34.  The most common clinical scenario presenting
with an elevated testosterone would be
secondary to exogenous androgen
administration
 uncommon clinical scenarios when endogenous
androgen excess may be the culprit.
◦ These include androgen resistance syndromes due to
androgen receptor defects
◦ Congenital adrenal hyperplasia,
◦ Leydig cell tumors,
◦ Adrenal tumors,
◦ hCG secreting tumors (testis, hepatoblastoma, lung,
or brain), and
◦ activating LH receptor mutations

35. Infertility Associated with
Exogenous Testosterone Therapy
 Exogenous testosterone administration acts as a
contraceptive agent as it inhibits LH and FSH secretion,
causing infertility secondary to reduced
spermatogenesis
 Treatment with testosterone can deplete intratesticular
testosterone and arrest spermatogenesis
 Therapy : ITT concentrations can be preserved during
periods of testosterone mediated gonadotropin
suppression using low-dose hCG therapy every other
day, with cessation of exogenous testosterone and
initiation of clomiphene citrate

36. Androgen Receptor Defects and
Androgen Insensitivity Syndromes
 The androgen receptor gene (AR) is located on the X-
chromosome; therefore, any mutation affecting the gene
will affect males. Females are carriers
 Over 600 mutations in the AR have been identified and
may lead to defective spermatogenesis and idiopathic
male infertility
 Androgen insensitivity syndrome (AIS) has an estimated
prevalence of 1 in 20,000 live male births

37. Congenital Adrenal Hyperplasia
 Patients with congenital adrenal hyperplasia often
have suppressed gonadotropins secondary to high
levels of adrenal androgens that are produced as a
result of defects in the cortisol production
 Although normally virilized, spermatogenesis is not
stimulated because FSH levels are low

38. Leydig Cell Tumors
 Leydig cell tumors are also a rare but well-
described cause of hypogonadism with normal
serum androgens and an elevated estradiol.
 In addition to spermatogenic disruption with
resultant infertility, feminization with gynecomastia
resulting from increased peripheral conversion of
testosterone to estradiol can be seen

39. WORK AROUND

42. Reference
 Cavallini, G., Beretta, G. (Eds.), 2015. Clinical Management of Male
Infertility. Springer International Publishing, Cham.
 Dohle GR, Arver S, Bettocchi C, Jones TH, Kliesch S, Punab M.
Guideline on Male Hypogonadism. European Association of Urology
2015
 Lipshultz, L.I., Howards, S.S., Niederberger, C.S. (Eds.), 2009.
Infertility in the male, 4th ed. ed. Cambridge University Press,
Cambridge, UK ; New York.
 Nieschlag, E., Behre, H.M., Nieschlag, S. (Eds.), 2010. Andrology.
Springer Berlin Heidelberg, Berlin, Heidelberg.
 Racowsky, C., Schlegel, P.N., Fauser, B.C., Carrell, D.T. (Eds.),
2011. Biennial Review of Infertility. Springer US, Boston, MA.
 Sabanegh, E.S. (Ed.), 2011. Male Infertility. Humana Press, Totowa,
NJ.
 Schill, W.-B., Comhaire, F.H., Hargreave, T.B. (Eds.), 2006.
Andrology for the clinician. Springer, New York, NY.