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1 A Scheme for Preconceptional Care to Prevent Fertility Disorders and Obstetric Complications
190 12 The Beneficial Effects of Preconceptional Normalisation of Folliculo-Luteal Function
3. Normalisation of folliculo-luteal function: the aim is to reach average luteal P
levels of 26–32 ng/ml (minimum 23 ng/ml) and an average luteal oestradiol of
400–450 pg/ml (but minimum 350 pg/ml and maximum 800–900 pg/ml).
Advising patients to use traditional contraceptive methods until FLF normalisation is achieved. During treatment, it is common that pregnancy takes place
before physiological FLF is achieved, which can lead to miscarriage, preterm
If the average baseline progesterone level is over 15 ng/ml, the recommended
initial dose is 5 × 50 mg clomiphene citrate (CC) (5 × 1 tbl. Clostilbegyt, EGIS,
Hungary) daily between the 5th and 9th days of the cycle, 5 × 100 mg if the baseline
average is under 15 ng/ml, together with regular control of the average luteal progesterone. After this, it is recommended to increase the CC dose by 5 × 50 mg per
cycle until the physiological P value is reached.
In cases where FLI is associated with hirsutism, or if the cycles are definitely
unstable, raromenorrheal or the patient responds poorly to CC (5 × 50 mg CC results
in less than 4–5 ng/ml increase in the average P), combining CC with low-dosage
corticoid treatment (LDCT) is recommended: administering 0.5 mg dexamethasone
(1tbl. Oradexon, Organon) every evening or if this is not available 4.0 mg methylprednisolone (1tbl. Medrol, Pfizer) provided that there is no contraindicating factor
present (diabetes, glucose intolerance, definite obesity). It is important to take the
corticoid drugs in the evening because cortisol is at its maximum level early in the
4. When the physiological levels of P and E2 are reached, we recommend repeating P and E2 measurements under constant treatment. These repeated measurements will show significantly different values (usually lower but sometimes
higher) in 15–20 % of patients. Knowing this, the treatment can be modified
accordingly (this generally occurs in highly reactive, temperamental women –
one who reacts intensely to everything will do so to stress effects also.) Lowdosage corticoid treatment usually stabilises the beneficial results in such cases.
If the patient responds to the same treatment with physiological values in one
cycle and an oestradiol level that is too high (>900 pg/ml oestradiol, <23 ng/ml
P) in the next, it is recommended to intercalate 1–2 months of contraceptive
treatment before restarting a lower dosage CC treatment, perhaps combined
with low-dosage corticoid. (Physiological FLF is produced ideally by three
dominant follicles with diameters >15 mm. This number increases in these
When the test results become repeatedly physiological, recommend conception
to the patient, with continued treatment. Due to reasons similar to those described
above, we recommend controlling P and E2 values every 3 months until pregnancy
occurs. Approximately 90 % of couples successfully conceive within 6 months with
physiological FLF and 98.5 % within a year. The time to pregnancy is 3.14 ± 2.4 cycles,
presuming that the partner has normospermia and the patient has at least one intact
12.1 A Scheme for Preconceptional Care
Table 12.2 Differential diagnostics of anovulatory disorders and amenorrheas (WHO)
Prolactin level determination
Elevated prolactin level
Normal prolactin level
Tumour No tumour
Considering the excellent monthly pregnancy rate (26.6 % on average over 12
cycles), insemination usually seems unnecessary. However, it might prove necessary in some cases, for example, after cervical surgery, with cervical stenosis and
after electrocoagulation or cryotherapy, if the cervical mucus production is minimal
or when the cervical canal remains narrow despite the applied laminaria dilation
and the cervical mucus is insufficient.
5. If conception fails to occur within 6 months with physiological FLF despite following the described therapeutic scheme, it is recommended to perform andrological
tests and fallopian tube permeability test while still maintaining therapy (monthly
pregnancy rates remain technically constant with physiological FLF even after 6
months). In the case of normospermia and at least one permeable fallopian tube
(with an isolateral ovarium), we can expect pregnancy to occur. Only 0.3–0.4 % of
couples fail to conceive within 15 months. A laparoscopy is suggested in these
cases (if the partner has normospermia) to reveal and resolve unknown causes,
adhesions, etc. If the laparoscopic results are normal, IVF can be recommended.
If the couple does not seek preconceptional medical advice, and the anamnesis
of the woman includes 1 year of infertility (6 months if the woman in question is
over 35 years), the presented scheme has to be preceded by andrological and tube
192 12 The Beneficial Effects of Preconceptional Normalisation of Folliculo-Luteal Function
6. Pregnancy fails to take place because of the lack of ovulation in a considerable
proportion of couples (20 %). In such cases it is reasonable to apply the therapyoriented differential diagnostic scheme issued by WHO (Lunenfeld and Eshkol
1979) (Table 12.2), which divides amenorrhea into seven classes based on the
pathogenetic cause, and thus the classification defines the required therapy at the
same time. For more details, see the relevant textbooks. To briefly summarise,
the correct classification can be made simply by measuring serum LH, FSH,
prolactin, E2 and, if needed, androgens.
The therapy-oriented classification of the hormonal causes of anovulation (WHO):
Class 1 Hypothalamic-pituitary insufficiency or hypogonadotropic hypogonadism
without compression of the hypothalamus or the pituitary
Amenorrhea, low FSH, LH and oestradiol levels, negative imaging results
of the hypothalamus and the pituitary.
Th. Gonadotropic treatment: FSH and LH mimetics
Rarely occurring form: our experiences show that after 2–3 months of sequential
hormone therapy, CC (or CC + DEX) treatment can normalise cycles (Chap. 3
Class 2 Hypothalamic-pituitary dysfunction or normogonadotropic hypogonadism
Eu-, raro- or amenorrhoea, physiological FSH, LH and oestradiol levels
Most often PCOS: anovulation, elevated serum androgens, ovarian ultrasound
image typical of PCOS (LH/FSH ratio usually over 2–3).
Less frequent simple regulatory disorder, without elevated androgen level and
PCOS-typical ovarian ultrasound image.
Clomiphene citrate treatment in appropriate dosage and/or low-dosage corticoid treatment, “hormonal wedge resection” in the case of PCOS
Class 3 Ovarian amenorrhoea or hypergonadotropic hypogonadism
Elevated FSH (>50 IU/l) low oestradiol resulting from the functional disability of the ovaries: they do not contain any primordial follicles that are capable
Ovulation induction is not possible; oestrogen-gestagen replacement is recommended to ameliorate complaints and oestrogen deficiency symptoms.
Class 4 Congenital or acquired anomalies of the genital tracts (uterine amenorrhea
or Asherman’s syndrome).
Amenorrhea, usually physiological hormonal levels, negative oestrogengestagen test
12.1 A Scheme for Preconceptional Care
No therapy available to promote conception
Class 5 Hyperprolactinaemic hypogonadism resulting from hypothalamic-pituitary
Amenorrhea, repeatedly elevated prolactin levels, tumour confirmed by
imaging (sella X-ray, CT, MRI); thyroid gland examination is necessary.
In the case of macroadenoma, surgery; in the case of microadenoma (diameter <10 mm) bromocriptine or other dopaminergic therapy.
Class 6 Hyperprolactinaemic hypogonadism without hypothalamic-pituitary
Amenorrhea, repeatedly elevated prolactin levels; imaging tests do not confirm tumour (sella X-ray, CT, MRI); TSH test is necessary.
Bromocriptine therapy or, in the case of intolerance, Norprolac treatment.
Class 7 Hypothalamic-pituitary insufficiency or hypogonadotropic hypogonadism
resulting from hypothalamic-pituitary compression
Amenorrhea, low FSH, LH and oestradiol levels, tumour confirmed by
Th. Surgical resolution of the compression
The vast majority of patients (approximately 80 %) with anovulation or amenorrhea
belong to Class 2. Another 15 % belong to Classes 5 and 6, while all other classes
account for about 5 % altogether. Most patients in Class 2 can be diagnosed with PCOS.
If the aforementioned treatments induce ovulatory cycles in anovulation or
amenorrhea, it is strongly recommended to perform the average luteal P test as we
presented. Ovulatory cycles induced thus are frequently associated with insufficient
FLF, which leads to further infertility, miscarriage and possibly preterm birth, etc.
By combining the chosen treatment with CC (e.g. bromocriptine), or increasing the
dose of the already applied CC treatment or the controlled complementation with
low-dosage corticoid administration, physiological FLF can be achieved in almost
all cases. PCOS treatment provides a great example of this. In their multicentered
study involving 376 patients treated with CC for PCOS, Legro et al. (2014a, b) ovulation was successfully induced in only 48.3 % of cycles (688/1425 cycles).
Pregnancy occurred in 14.9 % of ovulatory cycles (103/688). Miscarriage occurred
in 29.1 % of these pregnancies (30/103) and birth in 70.9 %. They started the treatment with the administration of 5 × 50 mg CC, and if ovulation failed to occur, they
increased the dose by 5 × 50 mg per cycle, up to 5 × 150 mg. The couples in the study
had confirmed normospermia and at least one intact tuboovarian unit. This example
clearly demonstrates the necessity of quantitative FLF examination.
194 12 The Beneficial Effects of Preconceptional Normalisation of Folliculo-Luteal Function
Davis OK, Berkeley AS, Naus GJ, Cholst IN, Freedman KS. The incidence of luteal phase
defect in normal, fertile women, determined by serial endometrial biopsies. Fertil Steril
Jones GS. Luteal phase defect: a review of pathophysiology. Curr Opin Obstet Gynecol
Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, Christman GM, Huang
H, Yan Q, Alvero R, Haisenleder DJ, Barnhart KT, Bates GW, Usadi R, Lucidi S, Baker V,
Trussell JC, Krawetz SA, Snyder P, Ohl D, Santoro N, Eisenberg E, Zhang H; NICHD
Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycystic
ovary syndrome. N Engl J Med. 2014a;371:119–29.
Legro RS, Zhang H; Eunice Kennedy Shriver NICHD Reproductive Medicine Network. Letrozole
or clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014b;
Lunenfeld B, Eshkol A. Therapeutically oriented classification of anovulation of neuroendocrine
or endocrine origin. In: Hafez ESE: Human ovulation. North-holland. 1979. pp 221–33.
Preterm birth, intrauterine growth retardation (IUGR) and preeclampsia (PE) are
probably the greatest challenges in obstetrics at this time. Their causes are basically
unknown; thus, their treatment and prevention are unresolved (Muglia and Katz
2010). These three forms of complication account for three quarters of foetal perinatal mortality; they are the leading cause of death, morbidity and disability among
newborns and children; and their adverse health consequences have lifelong effects
(Platt 2014). Their significance is further emphasised by the fact that their incidence
shows an increasing tendency even in developed countries such as the USA (where
the incidence of preterm births increased from 9.4 to 12.5 % between 1981 and
2004). Out of approximately 140 million births every year, 15 million end in preterm birth, 15 million newborns are retarded, there are 7 million cases of preeclampsia and more than 20 million planned clinical pregnancies end in abortion. About 8
million newborns die before the age of 1 every year (Muglia and Katz 2010); 3.1
million of them are solely attributable to preterm birth (Platt 2014). Mortality in
retarded babies is 4–8 times higher than in eutrophic newborns (Berkő and Joubert
2009). Preeclampsia still causes 50,000 deaths among mothers worldwide. With the
rapid development of neonatology, the survival rate of preterm infants has swiftly
increased. However, it has not been able to reduce the lifelong adverse health effects
of preterm birth and IUGR, and the number of disabled people has actually increased
significantly (Muglia and Katz 2010; Cosmi et al. 2011). Preterm birth significantly
increases the incidence of coronary diseases, stroke, type 2 diabetes mellitus, obesity, metabolic syndrome and osteoporosis later in life. It also increases the incidence of insulin resistance, glucose tolerance and hypertension as early as
prepubertal age or young adulthood (Barker 2006; Gluckman et al. 2008). Recurrent
miscarriage or habitual abortion (5 % of couples), unexplained infertility (5–6 % of
couples) and polycystic ovary syndrome (5–15 % of women) are also unresolved
problems. Infertility affects about 72 million couples worldwide at any given time
(Boivin et al. 2007). Obviously, we can provide a satisfactory solution for the problems described above only by appropriate treatment and prevention methods based
on the understanding of their underlying causes. The purpose of our work is to give
an overview of our observations regarding the causes of these problems as well as
the effective methods for their prevention and treatment.
© Springer International Publishing Switzerland 2016
G. Siklósi, Role of Folliculo-luteal Function in Human Reproduction,
According to international scientific societies on human reproduction and the
general view of experts, the confirmed presence of ovulation is sufficient for diagnosing a physiological menstrual cycle (ESHRE/ASRM 2012; ASRM 2012/a). The
presence and role of luteal insufficiency in human reproduction cannot be demonstrated (ASRM 2012/b). Our methods for the prevention and treatment of human
reproductive disorders described in this book were based on the recognition of the
fact that – contrary to the general concept – a significant proportion of ovulatory
cycles are not sufficient for conception and physiological reproduction, thus confirming that ovulation in itself is not enough to declare physiological cycles from
the aspect of reproduction. This opened the door for a new, unknown field – the very
important field of hormonal insufficiency of ovulatory cycles (folliculo-luteal insufficiency) – in which new relationships can be found that are very important for
studying, treating and preventing human reproductive disorders.
During human reproduction, the circumstances of implantation and the characteristics of the developed placenta (size, blood flow, functionality, etc.) are essentially determined by the characteristics of the endometrium, which are in turn
determined by hormones produced by the ovaries: the preovulatory oestradiol (E2)
and later the luteal progesterone (P) and E2 levels. Follicular E2 levels essentially
determine the histological features, thickness and blood supply of the proliferative
endometrium, the time and value of LH peak and thus ovulation and luteinisation.
Folliculogenesis, which is parallel to oocyte development, defines the final karyocytic and cytoplasmic maturation process. After these processes, depending on the
preovulatory E2 influence and the P levels, the secretory transformation of the
endometrium takes place, which eventually determines the conditions of placentation in a direct way (collectively: folliculo-luteal function/FLF). The characteristics
of the developing placenta determine the fate of the pregnancy. In physiological
circumstances, this process results in the formation of an oocyte and a placenta
capable of reproduction and finally in mature birth. But the varying degrees of FLF
insufficiency can cause the development of a more or less inadequate placenta and –
in more severe cases – the formation of an oocyte incapable of reproduction, thus
resulting in an adverse pregnancy outcome.
To clarify the role of FLF in human reproduction, it seemed necessary to determine the characteristics of physiological FLF first. Because of the considerable
individual variability in the hormonal levels of fertile women’s cycles, we considered a cycle to be definitely physiological if conception took place and was followed by birth. There is a 6-day-long progesterone (P) plateau between the 4th and
9th day after ovulation or before menstruation in physiological cycles. As the activity of the corpus luteum is the result of every preceding event in the cycle, we used
the value of the 6-day luteal progesterone plateau to quantitatively describe the
complete cycle. To reduce the diagnostic error (±49.8 %, 95 % CI) originating from
the markedly episodic secretion and the day-to-day variation of P, we defined luteal
function by the average of three P values obtained every other day during the P
plateau (Siklósi et al. 1984). This way, the physiological luteal P value proved to be
significantly higher (21.0 ± 2.0 ng/ml) than we previously thought (≥10 ng/ml).
After we recognised the strong relationship between FLI and pregnancy outcome,
we modified the P value considered as physiological. We deemed a cycle physiological, if conception took place, followed by the birth of a singular, mature and eutrophic newborn (P = 29.6 ± 3.3 ng/ml).
During our studies we observed that the characteristics of the endometrium – and
thus placentation also – are determined by FLF, which shows a strong correlation
with pregnancy outcome. While we can expect successful pregnancy if the placenta
is formed with physiological FLF, folliculo-luteal insufficiency (FLI) gives rise to
decreased placental capacity or even the complete failure of placenta formation.
Mild insufficiency of folliculo-luteal function (FLI Grade I) is the underlying cause
of slight placental impairment (preterm birth, IUGR and preeclampsia). Moderate
cases (FLI Grade II) result in more serious impairment (early or late miscarriage),
and the most pronounced form (FLI Grade III) leads to the formation of an endometrium inadequate for placentation (infertility). However, these observations can
only be verified by successful therapeutic results.
We investigated the effect of FLF normalisation on the pregnancy outcome in a
representative, unselected patient population (510 patients, 707 pregnancies) with
recurrent miscarriage. Based on the above, we presumed that insufficient placentation is the main cause underlying recurrent miscarriage (RM). The fact that the
luteal P (13.4 ± 3.3 ng/ml) in RM was significantly (p < 0.001) lower than the physiological values (13.4 and 29.6 ng/ml) also supports this hypothesis. Normalising
FLF prior to conception with controlled stimulation therapy resulted in a dramatic
decrease of the prevalence of abortion as well as preterm birth and IUGR, which
occurs 2–4 times more frequently in patients with recurrent miscarriage. The incidence of these complications is ten times lower than in the untreated control group
and 5–10 times lower than the national average. The strong correlation (r = 0.89,
p < 0.001) between the average luteal P and E2 levels characterising FLF and the
length of pregnancy (weeks) and the strong correlation (r = 0.78−0.90, p < 0.001)
between average luteal P and neonatal parameters (weight, length, weight percentile, BPD) both confirm our hypothesis. The major determining factor of pregnancy
outcome in RM is FLF, which essentially defines the conditions of placental
We assumed that in unexplained infertility (normospermia, at least one intact
tuboovarian unit and verified ovulation), the underlying cause is FLI of such severity that it causes the formation of an endometrium inappropriate for placenta formation, which is not recognised by the currently available diagnostic methods. This is
also supported by the significantly (p < 0.001) lower average luteal P values (11.3 ng/
ml) in UI compared to either the physiological values (29.6 ng/ml) or the values
obtained in RM (13.4 ng/ml). By normalising FLF with controlled stimulation treatment, the fertility of patients also normalised. Measured in a representative patient
population (621 patients, 838 pregnancies), the monthly pregnancy rate was 29 %
on average during the first 3 months, the 12-month average was 26.6 % and the
yearly cumulative rate was 98.5 %.
We investigated the relationship between FLF and pregnancy outcome in the
treatment of unexplained infertility (625 patients, 884 pregnancies). A significant
(p < 0.001) difference was found between the average P and E2 values of
pregnancies ending in miscarriage, preterm birth and mature birth. We also found
significant (p < 0.001) differences between the average P and E2 values measured in
the luteal phase of pregnancies ending in the birth of newborns with retardation and
of eutrophic newborns. Besides, a strong correlation (r = 0.89, p < 0.001) existed
between the average luteal P and E2 levels that describe FLF and the length of
pregnancy (weeks) as well as between FLF and neonatal parameters (newborn
weight, length, weight percentile and BPD) (r = 0.78−0.90, p < 0.001). In successful
pregnancies conceived with physiological FLF (P > 23 ng/ml), there were no cases
with developmental disorders, Down syndrome or other trisomy – including the
results of amniocentesis tests (N = 638). In such pregnancies, the prevalence of preterm birth, IUGR and miscarriage was significantly (p < 0.001) lower compared to
the national average, and preeclampsia did not occur at all. Preterm birth occurred
in 0.7 % (national prevalence 9.6 %) and intrauterine foetal growth retardation in
0.7 % (national prevalence 10.1 %). The prevalence of clinical abortion also
decreased significantly, to 3.4 % (95 %; CI, 2.3−4.7), while the national average is
15.1 %. These findings clearly suggest that the common cause underlying the aforementioned complications is FLI of varying degree.
Thus, the question arises, what could be the cause of the frequent occurrence
of FLI? Our studies have shown that the direct cause of FLI is stress, varying in
intensity and time, and/or being overweight, which gives rise to FLI depending on
individual reactivity. Continuous low-dosage corticoid treatment (0.5 mg dexamethasone per evening) in FLI significantly (p < 0.001) improved in FLF. Lowdosage dexamethasone therapy (or if unavailable, methylprednisolone therapy)
also proved to be a successful individual and adjuvant treatment for normalising
Assessing FLF seems inevitable in anovulatory disorders as well. Although in
PCOS, which is the most frequent anovulatory disorder occurring in 5–15 % of
women, ovulation can be successfully induced in 80 % of patients (with permeable
fallopian tubes and normospermia), half of the ovulating patients fail to conceive.
According to our studies, FLI underlies this phenomenon as well. We herewith
present the therapeutic method called “hormonal wedge resection” we developed
to treat PCOS. Using hormonal wedge resection, 97.6 % of patients (120/123)
achieved ovulation and (in the case of normospermia and at least intact tuboovarian
unit) 98.3 % of ovulating patients became pregnant (118/120), altogether 167
In recent years there has been an increasing trend for couples to put off having
children until later in life: the number of women giving birth at over 35 years of age
has doubled in the last 20 years. Meanwhile, the prevalence of infertility, miscarriage, preterm birth, IUGR, etc. significantly increases in women who are over 35.
During our studies (regarding recurrent miscarriage and infertility), we found that
the occurrence of the aforementioned complications in women who are over 35
(between 35 and 45 years) decreased to the same level seen in women who are
under 35 years old. At the same time, it was lower by an order of magnitude than the
national average. This suggests that it is not the oocyte aging, proportional to
maternal age that underlies these complications, but FLI of varying severity, which
occurs more and more often after 35 years of age. Thus, these complications can be
successfully prevented with FLF normalisation.
General conclusions can also be drawn from our findings obtained from our representative patient population. Normalising FLF is the most effective treatment for
recurrent miscarriage (5 % of couples), unexplained infertility (5–6 % of couples)
and PCOS (5–15 % of women). FLF assessment and normalisation is highly recommended before all future pregnancies if the history of the woman in question contains unsuccessful or complicated pregnancy or birth (early or late miscarriage,
preterm birth, IUGR, preeclampsia, foetal developmental abnormalities, trisomy,
etc.). Regular measurement and normalisation of FLF as part of the preconceptional
care would decrease the occurrence of the above complications by an order of magnitude and significantly reduce their severity. But is this just another costly method?
On the contrary, the prevention of these complications can be resolved at a fraction
of the cost of treating them.
In summary: the increasing occurrence of reproductive disorders as our civilisation goes forward is mainly caused by FLI, which results from stress of varying intensity and duration and/or overweight. The normalisation of FLF with
medication before conception allows us to almost fully cure and prevent reproductive disorders (recurrent miscarriage, unexplained infertility) and pregnancy
complications (preterm birth, IUGR, developmental abnormalities, etc.). By
regularly monitoring and normalising FLF, we may establish the birth of healthy
generations and significantly increase the national average number of births per
year (at least by 20–25 %). According to estimations, about 150,000 couples in
Hungary are currently trying to have a child without success. Their appropriate
care (with the presented simple, effective and low-cost methods) would significantly further improve the demographic situation of the country within several
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