Hormones and Infertility

By SP Rugera (Senior Lecturer)

MBARARA UNIVERSITY
Date: 06/05/2014

REFERENCES

INFERTILITY AND HORMONES:

http://www.fertility.com/international/ accessed 03.05.2014

TIETZ TEXTBOOK OF CLINICAL CHEMISTRY: Edited by Carl

Burtis, Edward R. Ashwood Third Edition Pages 1620-1627

A MANUAL OF LABORATORY and DIAGNOSTIC TESTS by

Frances Fischbach Pages 358-383

CLINICAL DIAGNOSIS AND MANAGEMENT BY LABORATORY

METHODS: Edited by John Bernard Henry 20th Edition Pages
304-332

INTRODUCTION

According to the World Health Organisation

(WHO), about 15% of couples of childbearing age
seek medical help for infertility
The problem can stem from both female and male
issues. Generally speaking, the source of infertility
is:

Exclusively with the female in about 30 - 40% of cases.

Exclusively with the male in about 10 - 30% of cases.
A combination of both partners having detectable
abnormalities in 15 - 30% of cases.

Percentage incidence of
causes of infertility

DEFINITION/OCCURENCE

Absence of pregnancy - one year of uninterrupted

sex (NO contraceptives)

Primary: No previous successful pregnancy (Now

unable to conceive)

Secondary: Previous successful pregnancy (Now

unable to conceive)

Occurrence: 50% of infertility of male origin

INTERLOCKING PLAYERS
The following are important players:
Woman's

ovulatory cycle

Production
Hormones

of sperm in the male

(gonadotropins) = affect
the ovaries and the testes

HORMONE PRODUCTION
SITES

REPRODUCTION
GONADOTROPINS
human

follicle stimulating hormone (hFSH)

(pituitary gland)

human luteinizing hormone (hLH) (pituitary

gland)
-Both under secretion control gonadotropinreleasing hormone (GnRH) (hypothalamus).

human

chorionic gonadotropin (hCG) placenta (maintains pregnancy after

implantation)

THE FEMALE AND MENSTRUAL

CYCLES
FEMALE SEXUAL
ORGAN

FEMALE SEXUAL ORGANS

THE FEMALE AND MENSTRUAL

CYCLES continued
Menstrual cycle occurs in three phases:
Follicular

phase: Days 1 to 13.

Ovulatory
Luteal

phase: Around day 14.

phase: Days 15 to 28.

THE FEMALE AND MENSTRUAL

CYCLES continued
The cycle controlled by hormones:

Follicle stimulating hormone (FSH)

Luteinizing

hormone (LH)

Oestrogen
Progesterone

THE FEMALE AND MENSTRUAL

CYCLES continued

FEMALE INFERTILITY
The following factors contribute:
ovarian (hormonal)
tubal
cervical
uterine
psychosocial
immunologic

FACTORS

continued

Factors contribution:
Ovulatory - 30% of all cases of
infertility
pelvic - 50%
immunologic - 5%.
Others - 15%

ENDOMETRIOSIS (causes
mechanical obstruction)

OVULATORY DYSFUNCTION
Can

develop regard less of normal

menses - dysfunction difficult to
diagnose.

Complicated

by many metabolic
diseases that affect ovulatory function.

There

are also diseases that tend to

increase androgen levels - include
Thyroid, liver disease as well as obesity.

HYPOGONADISM
Hypogonadism

(decreased functional
activity of the gonads) - also cause
infertility in the female

Either Hypergonadotropic or
hypogonadotropic (increased or
reduced gonadotropins)

REFERENCE VALUES
hCG

- absent in serum or urine not

pregnant
FSH Female
Follicular

Postmenopause

1.68-15 IU/L
21.9 56.6
0.61-16.3
14.2-52.3

Male

1.24-7.8

Ovulatory

peak

Luteal

REFERENCE VALUES continued

LH
Follicular

Postmenopause

1.37-9.9 IU/L
6.17 17.2
1.09-9.2
19.3-100.6

Male

1.42-15.4

Ovulatory

peak

Luteal

REFERENCE VALUES continued

Prolactin
Non

pregnant - 0-23ng/mL

Pregnant
Men

34-386 ng/mL

0-20 ng/mL

Children

3.2-20 ng/mL

REFERENCE VALUES continued

Testosterone
Men 270-1070 ng/mL
Children 0-20 ng/mL
Women 15-70 ng/mL

REFERENCE VALUES continued

Progesterone
Men

Less than 1.0ng/mL

Women
Prepubertal
Follicular
Luteal
First

timester
Second
Third

0.1-0.3 ng/mL
0.1-0.7 ng/mL
2-25 ng/mL
10-44 ng/mL
19.5-82.5 ng/mL
65-290 ng/mL

Hypergonadotropic
hypogonadism
Causes of hypergonatropic hypogonadism:

premature ovarian failure

gonadal dysgenesis (Turner syndrome and its

variants)

resistant ovary syndrome

menopause and

luteal phase deficiency.

Hypogonatropic
hypogonadism
Causes of hypogonatropic
hypogonadism:
pituitary or hypothalamic
insufficiency
hyperprolactinaemia.

LABORATORY ASSESSMENT
OF FEMALE INFERTILITY
Initial history + physical examination,
menstrual history important
Ovulation:
Infertile

despite clinically normal menstrual

cycles, or have amenorrhoea or oligonorrhoea.

Even

if cycle regular: determine whether

ovulation occurring + if luteal development is
normal.

Ovulation evaluation

Progestone level is the primary assay

Immediately after ovulation, progesterone levels

rise reaching a maximum after 5 days.
If ovulation does not occur, the expected rise is
lower than normal

Mid luteal phase levels are indicators:

>10ng/mL - Normal ovulation

<10ng/mL - Anovulation, inadequate luteal phase
progesterone production or inappropriate timing of
sample collection.

Ovulation evaluation

continued

Monitoring of basal body temperature:

Ovulation

produces a rapid rise in body

temperature of 0.5oF (persist through luteal
phase) - Temperature charts

This

is not helpful as it is retrospective (you

cannot use it to time the period of
intercourse that yields fertilization)

Ovulation evaluation

continued

Luteinising Hormone surge:

Luteinising hormone physiologically
appears in urine after a surge (24
36hrs before ovulation).
Useful in timing intercourse for
possible fertilization.
However does not confirm presence of
ovulation or the cause of anovulation.

Ovulation evaluation

continued

LH KITS TO TIME OVULATION

Physiological surge led to development of LH

hormone kits ACCURATE TIMING OF OVULATION
Uses dipstick with two site double monoclonal
enzyme linked antibody to detect presence of LH
in urine
A positive test indicates LH surge is occurring.
Predicts ovulation APPROX. 70% of cases.
Some studies show a 92% positive predictive
value with LH home kits for ovulation to occur
within 48 hours of a positive urine LH screen.

Evaluation of endocrine
parameter
Hypergonadotropic hypogonadism

Repeatedly elevated basal FSH trends (> 30 I U/L)

or a single elevation of >40 Iu/L indicates primary
ovarian failure

Estradiol levels of < 20 Iu/L (hypoestrogenic) are

evident in hypergonadotropic hypogonadism

Hyperprolactinaemia

Luteal phase deficiency is diagnosed when period

between ovulation and menses is 10 days or less.

Evaluation of endocrine
parameter continued
Hypogonadotropic hypogonadism
Estradiol

levels <40 pg/mL

Decreased

LH levels (< 10 Iu/L)

Decreased

FSH levels (< 10 Iu/L)

Hypothyroidism

MALE INFERTILITY
Hypogonadism

- results into lowered

testosterone levels - affects sperm
development (infertility)

Infertility

can be due either

hypogonatropic or hypergonadotropic
hypogonadism.

Factors leading to male

Infertility
These include Endocrine as well as non endocrine
:
Endocrine

Hypothalmic dysfunction: (majorly Kallmanns syndrome)

due to hypogonatropic hypogonadism whose causes include:
- GnRH deficiency and
-Hyper-prolactinaemia.
Deficiency of GnRH in hypothalamus causes Kallmanns syndrome.
Hyperprolactaemia impairs GnRH release - impotence. Drugs that
increase proclactin e.g. antihypertensive drugs also cause this
Pituitary dysfunction: Resulting majorly from surgery, radiation or
adenomas.

Factors leading to male Infertility

continued

Non direct endocrine:

Antibodies to sperms: Antibodies decrease motility;

cause agglutination - sperm failure.
Others:
Exogenous androgens,
thyroid disorders,
adrenal hyperplasia and testicular failure anatomic
abnormal spermatogenesis
psychosocial problems
Obesity in the infertility male (Gynaecomastia) sign of high concentration of oestrogen or most
likely testicular feminisation syndrome.

LABORATORY ASSESSMENT
OF MALE INFERTILITY

May detect early hormonal deficiency or distinguish

between testicular and pituitary causes.

Initial evaluation - detailed history of patient

targeting reproductive organs for evidence of proper
androgenisation (include medication/systemic illness
or potential toxin exposure)

The laboratory evaluation has three major aspects:

SEMEN ANALYSIS/ENDOCRINE
PARAMETERS/IMMUNOLOGICAL PARAMETERS

Semen analysis

ejaculate volume, pH, motility and motility direction

Parameter
Value
Ejaculate volume > 2 mL
Sperm Density
> 20 million/mL
Total sperm count > 40 million per ejaculate
Motility
> 50% forward (60 min
of ejaculation)
Morphology
> 30% normal
PH 7.2 8
Colour
Grey white yellow
Liquefaction
With in 40 min
Acid phoshatase 100-300g/mL
Others (Fructose, Citric acid, Inositol, Zinc, Magnesium,
Prostaglandins, glycerophosphorylcholine, Carnitine,
Glucosidase)

Endocrine parameters
Endocrine parameters
Serum

testosterone If male shows

evidence of deficient dev. of secondary
sex characteristics
Subject to Hcg stimulation (5000 IU Hcg)
Measure testosterone 48-96hrs later
Decreased testerone (infertilty)

Endocrine parameters
continued

Hypergonadtropic hypogonadism
FSH
-Should be measured in males with sperm counts
less than 5 10 million/mL.

-Elevated levels of FSH (sertoli cell dysfunction,

azoospermia, primary germinal cell failure or
genetic conditions e.g Klinefelters syndrome)

-Elevated FSH and LH with decreased

testosterone and oligospermia indicate primary
testicular failure (andropause)

Endocrine parameters
continued

Exogenous GnRH administration

Administered GnRH - distinguishes
between gonadal insufficiency
(pituitary failure or hypothalamic
failure)
FSH

levels are measured at 15, 30, 90

and 120 minutes after administration.

Endocrine parameters
continued

Interpretation of results:

No rise in FSH and LH indicates Pituitary failure.

Increase < 2times FSH levels from initial value and /or
maximum level does not exceed 3mIu/mL indicates relative
pituitary insuffiency.

Increase FSH levels to <3times the initial value and the

maximum does not exceed 9mIu/mL indicates occlusion of
sperm conveying structures (azoospermic patients) there is
need for a testicular biopsy for confirmation of diagnosis.

Increase FSH - >3times the basal levels and/or maximum

greater than 9 mIu/mL indicates exaggerated GnRH
response (masked hypergonadotropic hyponadism or in
adequate GnRH pulsability by the hypothalamus)

Endocrine parameters
continued

Immunologic parameters
Antisperm antibodies detected in the
techniques (agglutination, ELISAs RIAs, and
immunoflourescent)
Antibodies

on a carrier recognize any human

immunoglobin (antisperm antibodies) in the
serum.

High

percentage - cause is antisperm

antibodies.

SPECIAL HORMONAL OCURRENCES IN

THE FEMALE CONDITIONS OTHER THAN
INFERTILITY

AMMENORHOEA
Absence of menstrual bleeding in a
normal ovulatory menstrual cycle
Normal bleeding every after 28days
Varies

between 25 30 days in
healthy females

AMMENORHOEA
Primary

ammenorrhoea - NO spontaneous
periodic menstruation by the age of 16 years
(with/out female secondary sexual xteristics)
Secondary ammenorrhoea refers to
absence of periodic menstruation for
at

least 6 months in a female - previously

experienced menses
12 months in females with a history of
oligomenorrhoea or infrequent menstruations
(less than 9 times in a year)

AMMENORHOEA

continued

Cause of ammenorrhoea (usually overlap):

Pregnancy( chorionic gonadotrophin antibodies in urine - pregnancy test)

Lower tract defects (viginal aplasia, imperfolate hymen, congenital, vaginal

atresia), uterine disorders, ovarian disorders (various syndromes including
Turners, testicular fertilization, polysystic ovary), adrenal disorders
(congenital adrenal hypoplasma) hypothyroidism, pituitary- hypothalam ic
disorders (hypopitutation, Kallmanns syndrome)
Secondary ammenorrhoea include: uterine disorders (post traumatic,
progestational agents) ovarian disorders (polycystic ovary syndrome,
ovarian tumors, premature ovarian failure) adrenal hyperplasia, cushings
syndrome, hypo/hyperthyroidism, tumors of the hypothalamus, stress e.t.c.
Hyperprolactinaemia is an important cause of ammenorrhoea. High plasma
prolactin levels inhibit the normal pulsatile release of GnRH and inhibit
gonadal steroid hormone synthesis directly. This causes low gonadotrophin
and oestrogen levels and symptoms of oestrogen deficiency.
NOTE: INTEPRETE hyperprolactinaemia with caution. Samples should be
taken 2 3 hours after waking up. Even minor stresses e.g. during
venepuncture or drugs e.g. methyldopa and patients on estrogen seem to
affect it (increase)

CROSS CUTTING SPECIAL CASES:

HIRSUTISM AND VIRILISATION
HIRSUTISM
Excessive growth of terminal hair on girls,
boys and women in a distribution similar to
that occurring in post pubertal men
True hirsutism occurs in women and
evidenced by increase in androgens.
However idiopathic hirsutism occurs at a
rate of 50% in all hirsute women. In such
cases normal physical and laboratory
findings are evident

HIRSUTISM continued

Testosterone is the most important hormone. In normal

women, about half the plasma testosterone comes from the
ovary, both by direct secretion and by peripheral conversion
of androstenedione. The rest is derived from peripheral
conversion of adrenal androstenedione and
dehydroepiandrosterone (DHEA)

Evaluation of both disorders is through estimation of both

testosterone and DHEA. High DHEA-S suggest the
androgens are of adrenal origin whereas high testosterone
suggests either an adrenal or ovarian source (but majorly
ovarian).

In hirsutism, plasma LH is increased with a high LH to FSH of

usually greater than 3:1. Plasma testosterone levels are
high. This is sometimes accompanied by raised levels of
prolactin.

VIRILISM
Virilism

is a serious case than hirsutism

Also associated with increased androgen levels
Identified by
enlargement

clitoris,
Increased hair growth of male distribution
deepening of voice and breast atrophy
Main causes - ovarian tumors which secrete androgens
mainly testosterone and adrenocortical pathology
especially tumors e.g pituitary dependent cushings
syndrome (although rarely). There is a rise in DHEAS