Female subfertility: a first sign of metabolic and cardiovascular anomalies?

Overall, 10 * 15% of couples seek specialist help once in their lives when a
spontaneous pregnancy does not occur. These couples are defined subfertile when
there is at least one year of unprotected intercourse without conceiving.
Subfertility can have different causes. A basic fertility work-up focuses on
the reproductive system of the couple. After this basic fertility work up the
subfertility remains unexplained in 16-24% of the couples. We hypothesize that
cardio-metabolic and hemodynamic abnormalities reducing cardiovascular reserves
relate to circulatory redistribution at the expense of uterine perfusion and
with it women*s fertility. This could especially be important in the subgroups
with an unexplained subfertility and a decreased ovarian reserve. For all
possible assessed abnormalities, proven effective treatments are available such
as primarily life style corrective actions. Furthermore these interventions
could lead to better results in fertility treatment, better obstetric outcome
and reduced life long health risks.

The overall objective of this study is to examine specific cardio-metabolic and
cardiovascular parameters in women of subfertile couples. This study protocol
is divided in 3 studies to evaluate several cardio-metabolic/cardiovascular
parameters in different subgroups of female subfertility compared to fertile
women.

- Study 1 *The metabolic syndrome and female subfertility*: To evaluate the
prevalence of metabolic syndrome in all women who are assessed for
subfertility. We will also study this prevalence in diverse subgroups as
identified by their cause for the subfertility as compared to fertile women.

- Study 2 *The cardiovascular profile in female subfertility*: To study if
women with female subfertility classified as unexplained or *expected*
decreased ovarian reserve have a less favourable cardiovascular profile than
fertile women. For this study we want to evaluate the uterine artery
pulsatility index (PI) as measure of uterine perfusion, the plasma volume as
measure of venous reserve capacity, the intima media thickness of the carotid
arteries as proxy of chronic strain and the endothelial function, measured by
flow mediated dilatation (FMD) of the brachial artery.

- Study 3 *The cardiovascular profile of women with a poor ovarian response*:
To study if women of an IVF population with a *proven* decreased ovarian
reserve have a less favourable cardiovascular profile than healthy women.
With these different studies, we hope to identify possible
cardio-metabolic/cardiovascular causes for female subfer tility. This can lead
to new treatment options for female subfertility, enhancing reproductive and
obstetric outcome, and a risk assessment for later in life.

Cross-sectional studies

Study 1: The study of the metabolic syndrome can be synchronized with the basic
fertility work- up. Most measurements can be performed on days they have
regular examinations for their basic fertility work up. The extra blood samples
can be taken on menstrual cycle day 3 when the patient already needs to give a
regular blood sample for hormonal status. These blood samples need to be taken
in a fasting state of the patient. Patients have to collect a morning urine
sample for measurement of albuminuria on cycle day 10, the day they come for a
regular ultrasound. The measurement of blood pressure for half an hour can be
combined with the bloodsampling on cycle day 3, because the blood pressure must
be measured in the follicular phase (before menstrual cycle day 7). Other
measurements necessary for the metabolic syndrome (BMI, waist and hip
measurement, questionnaire) are part of the regular basic fertility work-up.
All the extra measurements for metabolic syndrome are easily combined with the
regular clinical work up and do not induce extra risks for the patient.

Study 2: For the second study the measurements of the uterine artery
pulsatility index, the plasma volume, the intima media thickness (IMT) and the
endothelial function (FMD) need to be performed before patients start hormonal
treatment. For the measurement of the uterine artery pulsatility index patients
need an extra hospital visit between menstrual cycle day 3 and 7 for a
transvaginal ultrasound. This ultrasound gives no extra risk for the patient.
This visit can be combined with the measurements of the IMT and the endothelial
function and is scheduled for 2 hours. The intima media thickness and
endothelial function will be measured by an experienced researcher (E. Mulder
or V. Lopes van Balen). The IMT measurement is performed within 10 minutes and
not invasive. For the measurement of the flow mediated dilatation a blood
pressure cuff will be put on the fore arm and the pressure will be increased
until 200 mm Hg for 5 minutes. These 5 minutes can be slightly uncomfortable
for the patient. After this first measurement the patient receives sublingual
nitrate, which causes vasodilatation. Then the IMT measurement will be repeated
to differentiate between endothelial dependent and independent vasodilatation.
The patient can experience harmless side effects due to the vasodilatation like
headache, short moment of weakness or short drop of the blood pressure.
Overall, women endure this examination well. The measurement of the plasma
volume takes place on the Nuclear Department. For this measurement 5 microcurie
radioactive iodine-125 albumin will be injected. The radiation of iodine-125 is
very small (< 0,1 microsievert), even less than the received radiation from a
flight. Radiation is a natural phenonomen which is all around us, in our food,
the ground and in the air. The small dosage used for the measurement of the
plasma volume gives no extra risk for diseases or adverse effects for the
patient and is a routine performed measurement in the Nuclear Department. The
injection of the radioactive albumin can give a cold feeling at the place of
the injection, because it has to be saved in a refrigerator. After the
injection in one arm three venous samples need to be taken from the other arm
(from one inserted venous canula). Incidentally, this venapuncture can lead to
a hematoma. Apart from sporadic extravasation or inability to collect blood,
the last 20 years of invasive plasma volume measurement in our clinic has not
led to any serious adverse events.

For the patients in study 3, who had an IVF treatment in the period of 2010 *
2013, this study implies they have to come back for one or two hospital visits.
The same examinations as described in study 2 will be performed.