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1 Folliculo-Luteal Insufficiency Is the Main Cause of Unexplained Infertility

1 Folliculo-Luteal Insufficiency Is the Main Cause of Unexplained Infertility

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106



6



Unexplained Infertility and Folliculo-Luteal Function



in the andrological test results. We used the 2-year criteria for the diagnosis of infertility. Although these criteria have since been modified to 1 year (ASRM 2008), for

the sake of consistency, we only analysed and processed the data of patients with at

least 2 years of infertility. While the treated group (N = 658) received controlled

clomiphene citrate (CC) (Clostilbegyt, EGIS, Hungary) and/or low-dosage corticoid treatment, the untreated control group (N = 147) did not receive any treatment

following examinations. Patients who, despite our recommendation, failed to show

up for treatment were asked in letters about their further reproductive medical status. Patients who did not receive any treatment for 8 years after the examinations –

but still desired to have a child –composed the untreated control group.

Out of the 658 patients, 33 quit treatment during the first 12 cycles, and the

remaining 625 patients conceived 615 pregnancies. We offered alternative therapy

to the ten patients who failed to become pregnant over 12 months, but nine out of

them chose to continue the treatment. Conception occurred in a further six patients

during the 13th to 15th cycles, thus in a total of 621 cases during the first treatment

periods. Later on, 220 patients showed up for repeated treatment, out of which 6

stopped therapy within 12 months and pregnancy occurred in 214 patients.

Altogether, out of the initial 658 patients, we achieved 853 pregnancies in 621

patients.



6.1.2



Treatment Protocol



In the treated group, we applied clomiphene citrate (CC) (Clostilbegyt, EGIS) and/

or low-dosage corticoid treatment together with the regular control of luteal P. We

applied CC treatment between the 5th and 9th day of the cycle, with an initial dose

of 5 × 100 mg if the progesterone level was below 15 ng/ml and 5 × 50 mg if the P

value was over 15 ng/ml. We increased the dosage with 5 × 50 mg per cycle until we

reached the physiological average (21.0 ng/ml) or the physiological minimum

(17 ng/ml). Low-dosage corticoid treatment was used in the form of continuously

administered 0.5 mg dexamethasone every evening or in the absence of this, 4 mg

methylprednisolone (Medrol, Pfizer) (Chap. 4). After we recognised the strong relationship between pregnancy outcome and average luteal P, our applied physiological luteal values needed revising. We considered the P value of cycles resulting in

the birth of a mature, eutrophic and singular newborn as physiological: 29.6 ± 3.1 ng/

ml. We recommended that patients use traditional contraceptive methods until the

achievement of the physiological value. We advised patients to get pregnant only

after the physiological value was achieved, along with the continued application of

the dosage required for normalisation. We did this because on several occasions, a

patient conceived during the treatment before she achieved physiological FLF and

the pregnancy aborted.

The main goal of our study was to investigate the monthly pregnancy rate (MPR),

cumulative pregnancy rate (CPR) and the time to pregnancy (TTP) with physiological FLF in patients receiving UI treatment. In addition, we examined the relationship between FLF and pregnancy outcome.



6.1



Folliculo-Luteal Insufficiency Is the Main Cause of Unexplained Infertility



6.1.3



107



Results



The characteristics of the treated and untreated groups are summarised in Table 6.1.

There was no significant difference between the patient characteristics of the two

groups. The infertility period was an average of 4.4 and 4.2, respectively, in the two

groups.

The baseline average P values of the patients between the 4th and 9th days before

menstruation (11.3 ± 3.3 ng/ml; average ± SD, N = 658) were significantly lower

than the established physiological value (21.0 ± 2.0 ng/ml). The baseline P value

failed to reach 10 ng/ml in 36.6 % of patients.

The monthly pregnancy rate (MPR) (including patients who stopped treatment in

the meantime) was an average of 28.9 % during the first three cycles, and the average over 12 months was 26.6 % (Table 6.2). Cumulative pregnancy rate (CPR) over

3, 6, 9 and 12 months was 64.1 %, 82.5 %, 90.3 % and 93.5 %, respectively (Fig. 6.2).

In patients who continued treatment for 12 months (N = 625), the CPR of 12 months

was 98.4 % during the first treatment period. Time to pregnancy (TTP) with physiological FLF in patients who successfully conceived during the first treatment

period (N = 621) was 3.14 ± 2.4 cycles. In the case of repeated pregnancies, these

values were significantly better (Table 6.3).

In the untreated control group (N = 147), 102 pregnancies were conceived in 72

patients (49 %) over 8 years. In this group, CPR over 6 and 12 months was 8.8 %

and 13.6 %, and 49 % over the total of 8 years.

For primary and secondary infertility, there was no significant difference in the

TTP value with physiological FLF during the first pregnancies: 3.14 ± 2.4 and

3.14 ± 2.5 cycles (average ± SD), and we did not find significant differences between

the yearly CPR values of the two groups (98.2 and 98.9 %).

At the same time – either in the case of primary or secondary infertility – a significant (p < 0.001) difference was found between the TTP values of first (N = 621)

Table 6.1 Baseline characteristics of patients



Variables*

Age, years – average ± SD

Range

>35 years – N (%)

Body mass index – kg/m2

Infertility length years, average ± SD

Range

Primary infertility

Secondary infertility

Miscarriage in the anamnesis

Birth in the anamnesis

Baseline progesterone value: ng/ml



Treated group average

P > 17 ng/ml

N = 658

30.3 ± 4.5

20–45

111 (18 %)

22.4 ± 3.5

4.4 ± 2.4

(2–17)

377 (57 %)

281 (43 %)

131 (21 %)

91 (15 %)

11.3 ± 3.3



*The difference in the characteristics of the two groups is not significant



Untreated control

group

N = 147

30.3 ± 4.8

20–45

28 (19 %)

22.7 ± 2.6

4.2 ± 2.2

(2–14)

85 (58 %)

62 (42 %)

41 (28 %)

22 (15 %)

10.8 ± 3.4



108



6



Unexplained Infertility and Folliculo-Luteal Function



Table 6.2 Pregnancy rates with physiological folliculo-luteal function (p > 17 ng/ml) during the

first treatment

Cycle

number

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

Total



Number of

cycles

(patients)



Dropout

patients



No. of

pregnancy



Monthly

pregnancy rate



658

496

351

232

171

126

94

68

49

33

22

14

2,314



0

0

4

6

6

5

4

2

4

1

1

0

33 (5.0 %)



162

145

115

55

39

27

22

17

12

10

7

4

615



24.6

29.2

32.8

23.7

22.8

21.4

23.4

25.0

24.5

30.3

31.8

28.6

Average: 26.6 %

615/2,314



100



Cumulative

pregnancy rate

24.6

46.7

64.1

72.5

78.4

82.5

85.9

88.4

90.3

91.8

92.9

93.5



%



90



2



3



1



80

70

60

50

40

30



4



20

10

0



0



3



6



9



12



15



18



21



24



months



Fig. 6.2 Cumulative pregnancy rates. (1) Cumulative pregnancy rates deemed physiological. (2)

Cumulative pregnancy rates of first pregnancies with physiological FLF. (3) Cumulative pregnancy rates of repeated pregnancies with physiological FLF. (4) Cumulative pregnancy rates in UI

without treatment



and repeated (N = 214) conceptions with physiological FLF (3.14 ± 2.4 and

2.56 ± 2.0 cycles, p < 0.001). The monthly pregnancy rate of repeated treatments was

42.1 % on average (177 pregnancies/419 cycles) during the first three cycles, and the

yearly average was 38.4 % (214 pregnancies/560 cycles). The cumulative pregnancy



6.1



Folliculo-Luteal Insufficiency Is the Main Cause of Unexplained Infertility



109



Table 6.3 Pregnancy rates with physiological folliculo-luteal function (p > 17 ng/ml) during

repeated treatment

No. of

cycle

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

Total



Number of

cycles

(patients)



Dropout

patients



Number of

pregnancies



Monthly

pregnancy rate



220

128

72

42

30

23

15

12

8

5

2

1

558



0

0

1

2

1

0

1

1

0

0

0

0

6 (2.7 %)



92

56

29

10

6

8

2

3

3

3

1

1

214



41.8

43.8

40.8

25.0

20.7

34.8

14.3

27.3

37.5



Cumulative

pregnancy rate

41.8

67.3

80.5

85.0

87.7

91.4

92.3

93.6

95.0

96.4

96.8

97.3



Average:

38.4 %

214/558



rate (CPR) over 3, 6, 9 and 12 months was 80.5, 91.4, 95.0 and 97.3 %. However,

there was no significant difference between the yearly CPRs of patients who

received continued treatment for 12 months the first time or repeatedly (98.4 and

100 %).

When we investigated the pregnancy rates by patient age, we did not find any

considerable difference. There was no significant difference concerning the yearly

cumulative pregnancy rate of the patient group under 35 years and at least 35 years

of age (98.5 and 98.4 %), and the time to pregnancy also did not differ in the case of

physiological FLF (3.14 ± 2.4 and 3.22 ± 2.3 cycles) between the two age groups. In

detail: the TTP values of first pregnancies were 3.08 ± 2.3 cycles under 30 years of

age, 3.11 ± 2.5 cycles between 30 and <35 years, 3.44 ± 2.6 cycles between 35 and

<40 years and 3.05 ± 2.1 cycles for 40 years or more.

When we analysed the TTP after ≤4 years (2–4 years) of infertility and after

>4 years (5–17 years) of infertility, we found a significant (p < 0.001) difference

even in the case of physiological FLF during the first pregnancies: 3.69 ≤ 2.7 cycles

and 2.83 ≤ 2.2 cycles. However, the yearly cumulative pregnancy rates of the two

groups were similar (98.5 and 98.1 %).

In about one-fifth of the patients (20.1 %), an intact and permeable oviduct was

only unilaterally detected (HSG, laparoscopy) or they underwent unilateral salpingectomy (intact tuboovarian unit only on one side). In the case of physiological

FLF, the time to pregnancy differed only slightly (3.5 ± 2.5 and 3.2 ± 2.3 cycles, NS),

and the yearly cumulative pregnancy rates were also similar (97.6 and 98.5 %).

Septated, subseptated and bicornuate uterus occurred in 24 cases (4.7 %) in our

patient population. Altogether 33 pregnancies were conceived with physiological

FLF in the 24 patients and every one of them ended with mature birth.



110



6



Unexplained Infertility and Folliculo-Luteal Function



Forty-two of our patients had 2–7 unsuccessful IVF treatments because of UI in

their anamnesis; all patients conceived with physiological FLF, and except in one

case, their pregnancies resulted in mature birth.

We found that the prevalence of unexplained infertility in 1,000 unselected, successive couples suffering from infertility was 32.2 %. According to the general

view, patients are categorised into UI if – together with normospermia and verified

ovulation – both oviducts are permeable. According to this definition, the prevalence of UI would be 25.7 % in our patient population. Seeing our initial positive

therapeutic results, we considered couples to have UI also if only one intact tuboovarian unit was detectable (intact, permeable oviduct with isolateral ovarium) as

well. As can be seen from our reported therapeutic results, this approach proved to

be correct.

Pregnancy outcomes regarding untreated pregnancies and pregnancies conceived with physiological FLF are summarised in Table 6.4 in comparison with the

average incidence of obstetric complications in Hungary. Pregnancy outcomes were

significantly more favourable with physiological FLF than in the untreated group

and also than the national average.

The birth rate in the case of physiological cycle (P > 17 ng/ml) was significantly

(p < 0.001) higher (95.2 %) than in the untreated control group (52.9 %) and in the

national population overall (83.8 %). At the same time, the incidence of miscarriage

was significantly (p < 0.001) lower in the case of physiological cycles (3.2 %) than

in the untreated group (41.2 %) and in the whole national population (15.1 %). On

the other hand, the occurrence of preterm birth, IUGR and the birth of newborns

under 2,500 g was considerably decreased in the case of physiological cycles compared to the other two groups. There were 27 miscarriages in our patient population,

all of them in the first trimester (≤14 weeks). We successfully repeated treatment in

17 of 27 patients altogether 25 times, with a result of 23 births (two twin births), one

extrauterine pregnancy and in one case, abortion, after which the latter patient gave

birth successfully at term after her next pregnancy. Down syndrome did not occur

in the births of our patient population (the results of amniocentesis tests are included

here).

Twin birth occurred in 40 cases (5.0 %), out of which 10 were preterm births and

seven were IUGR. Twin births took place between the 34th and 40th week

(37.5 ± 1.6 weeks); the average weight of newborns was between 1,770 and 3,660 g

(2,498 ± 384 g) and was under 2,000 g in three cases. No triplets were born

(Table 6.4).



6.2



Discussion



Our therapeutic results appear to confirm that the average of three P values measured between the 4th and 9th day after ovulation or before menstruation are appropriate to quantitatively describe FLF. However, our treatment results support that

the physiological luteal P values are considerably higher than we previously

assumed (P ≥ 10 ng/ml, ESHRE 1996). Initially we considered the P values typical



41.2 %

42/102

5.9 %

6/102

52.9 %

54/102

69.8 %

37/53

30.2 %

16/53

30.2 %

16/53

35.8 %

19/53

11.3 %

6/53

5.6 %

3/54

1.9 %

1/54

1/1 1/1

1/1







NS



p < 0.01



p < 0.001



p < 0.001



p < 0.001



p < 0.001



p < 0.001



p < 0.001



p < 0.01



p < 0.001



Significance*

3.2 %

27/835

1.5 %

13/835

95.3 %

795/835

97.7 %

738/755

2.3 %

17/755

3.4 %

26/755

4.2 %

32/755

0.13 %

1/755

0.5 %

4/79

5.0 %

40/795

10/40 7/40

22/40





Treated group

P > 17 ng/ml

n = 835



6.3 %

38/606

9/38 7/38

7/38





3.4 %

22/638

1.6 %

10/638

95.0 %

606/638

99.3 %

564/568

0.7 %

4/568

0.7 %

4/568

1.0 %

6/568

0.17 %

1/568





Treated

group

P > 23 ng/ml

n = 638



12.2

3–53

3.5

0.5–26



19.6

11–35

3.9

1.4–11

16.8

10–29

60.9

19–191

60.9

19–191

60.9

19–191

52.3

19–139



Odds

ratio

95 %

CI**



1.6 %



1.6 %



9.3 %



10.1 %



9.5 %



90.5 %



83.8 %



1.1 %



National

average

15.1 %



Discussion



*Significance between the untreated and the treated group (p > 17 ng/ml)

**Odds ratio between the untreated and the physiological value group (p > 23 ng/ml)



Variables

Abortion/pregnancy

Patients

Extrauterine pregnancy/

Pregnancy − patients

Birth/pregnancy

Patients

Birth/singular pregnancy

Patients

Preterm birth/singular pregnancy

Patients

IUGR/singular pregnancy

Patients

Birth weight <2,500 g/

/Singular pregnancy − patients

Birth weight <1,500 g/

/Singular pregnancy − patients

Preeclampsia/pregnancy

Patients

Twin birth/birth

Patients

Preterm birth, IUGR,

Birth weight <2,500 g

Triplet birth/

/Birth



Untreated control

group

n = 102



Table 6.4 Pregnancy outcomes in unexplained infertility

6.2

111



112



6



Unexplained Infertility and Folliculo-Luteal Function



for total births (21.0 ng/ml, physiological minimum 17 ng/ml) as physiological. The

strong correlation between luteal P levels and pregnancy outcome lead us to modify

the characteristics of FLF. After the significantly (p < 0.001) favourable outcomes of

pregnancies, we considered the average values of luteal P (29.6 ± 3.1 ng/ml, physiological minimum value 23 ng/ml) in pregnancies resulting in singular, mature and

eutrophic newborns as physiological from the aspect of reproduction, in order to

reduce the incidence of preterm birth, IUGR, etc. The results achieved in UI seem

to support this consideration.

We failed to demonstrate a significant difference between the two minimum values regarding fertility (17 and 23 ng/ml). Pregnancy rates were similar in the two

patient groups with regard to monthly and cumulative pregnancy rates as well as to

time to pregnancy (3.16 ± 2.7 and 3.14 ± 2.3 cycles). Meanwhile, we found a difference between the two physiological minimum values regarding the occurrence of

preterm birth, IUGR and other complications, similarly to the results of patients

with recurrent miscarriage. Other researchers also detected similar P values in physiological cycles and in UI (24.0 and 13.7 ng/ml, Leach et al. 1997). A likewise

physiological minimum value (18 ng/ml) was applied during FLI treatment by

Dickey and Holtkamp (1996) Dickey et al. (2002). Dickey and Hower (1995) found

a luteal P value almost identical to our results in successful pregnancies: their luteal

average value was 27 ng/ml in spontaneous cycles and a luteal average of 32 ng/ml

in CC-treated cycles when pregnancy ended in term birth.

Our therapeutic results appear to confirm our original hypothesis that the main

cause of UI is the hormonal insufficiency of the ovulatory menstrual cycle. Even

when ovulation occurs, low preovulatory oestradiol (E2) and then insufficient luteal

P and E2 levels can lead to the formation of a deficient secretory endometrium that

is inappropriate for implantation and placentation (folliculo-luteal insufficiency,

FLI). With adequate treatment, preovulatory oestradiol is produced in an appropriate amount and generates an adequate oestradiol peak, which in turn induces an

adequate sized LH peak in the optimal karyotic and cytoplasmic maturity stage of

the oocyte. Subsequently, the physiological level of luteal P that follows the adequate E2 effect ensures that the endometrium is appropriate for implantation and

placentation.

Most authors have established the physiological value of monthly pregnancy rate

as being 20 % on average (ESHRE 2000; Evers 2002; RCOG 2004; Thoma et al.

2013), which corresponds to the yearly cumulative pregnancy rate of 80 % that is

generally accepted as physiological. This value stays around 50 % during the second

year and then declines to a yearly 10–12 %, and after 3 years, it decreases by 24 %

per year (ESHRE 1996), and eventually, the chance of spontaneous pregnancy is

negligible after 10 years (Mansour et al. 2011). In the case of secondary infertility,

these pregnancy rates are almost 80 % better after 2 years (Collins and Rowe 1989).

Even more favourable pregnancy rates were achieved in natural family planning

programmes. Gnoth et al. (2003, 2005) obtained a cumulative pregnancy rate of

92 % in 340 couples and 98 % in the ascertained fertile group (where pregnancy

occurred) within 1 year. The time to pregnancy was 3.56 ± 4.03 months in the latter

group.



6.2



Discussion



113



The definite FLI after UI for at least 4 years on average in our patient population

seems to explain the cumulative pregnancy rates obtained in the untreated control

group (8.8 % over 6 months, 13.6 % over 12 months and 49 % over 8 years). The

average luteal P (11.3 ± 3.3 ng/ml) in UI was significantly (p < 0.001) lower than the

physiological values we established. With FLF normalised by controlled treatment,

the fertility of the patients also became normal despite the relatively long infertility

period (average 4.4 years). The monthly and cumulative pregnancy rates with physiological FLF almost attained the favourable pregnancy rates noticed in natural

family planning programmes. MPR during the first 3 months was an average of

28.9 % and an average of 26.6 % over a year during the first treatment. These values

were even better during repeated treatment (42.1 and 38.4 %).

CC treatment is widely used for the treatment of UI, but in most cases in fixed

doses of 5 × 50 or 5 × 100 mg (so-called empirical treatment). A MPR of 7–13 %

(Reindollar et al. 2010; Hatasaka 2011) is usually reached during the first 4–6 cycles

with such therapy, with this value decreasing dramatically over the course of further

cycles. But the individual effect of CC is extremely variable (Dickey and Holtkamp

1996). In our studies, only about half of the patients achieved normal average luteal

P levels as a result of 5 × 100 mg CC (Chap. 5), which explains the poor results of

fixed-dose CC therapy. A MPR around 15–20 % over 12 cycles is obtained by

researchers who control the effect of CC by singular P determination and increase

CC dose until P exceeds 18 ng/ml (Dickey et al. 2002). The more favourable MPR

we obtained (26.6 %) presumably originates from our more exact determination of

average luteal P. Taking the remarkably episodic P secretion (±40.3 %) and its dayto-day variation (±49.7 %) into consideration, a single P value of 18 ng/ml means

only that the actual mean luteal P is between 9 and 27 ng/ml (95 % CI), that is to say,

it remains under 17 ng/ml in a good proportion of patients. Our results regarding the

fertility of patients who completed the first treatment approach the values found by

other researchers (Gnoth et al. 2003, 2006) in “actually fertile couples” (where

pregnancy occurred) in natural family planning programme: MPR 26.6 and 30 %,

CPR over 12 cycles 93.5 and 98 %, TTP 3.1 ± 2.4 and 3.5 ± 4.0 cycles.

Spontaneous pregnancy rates in UI are essentially determined by two factors: the

patient’s age and the length of infertility. It is a general observation that fertility

considerably decreases in parallel with age – especially in over 35 s – in spontaneous cycles, stimulated cycles with insemination and in IVF as well (Guzik and

Zeleznik (1990); ESHRE 2005; Balasch and Gratacós 2011; Nelson et al. 2013;

Thoma et al. 2013). While the rate of infertility is 10 % between the age of 20 and

28 years, it is 25 % in women of 35 years of age (Ray et al. 2012; Hull 1992;

Schmidt et al. 2012). However, the fertility of patients normalised, regardless of the

length of the infertile period, in the case of physiological FLF. With physiological

FLF, we failed also to demonstrate a significant difference in the TTP depending on

the patients’ age. The TTP of the first pregnancies was 3.08 ± 2.3 cycles under

30 years, 3.11 ± 2.5 cycles between 30 and 35 years, 3.44 ± 2.6 cycles between 35

and 40 years and 3.05 ± 2.1 cycles in the case of 40 years or more.

Another important factor in the occurrence of spontaneous pregnancy in UI is the

length of the infertile period. The chance of conception declines in parallel with the



114



6



Unexplained Infertility and Folliculo-Luteal Function



length of infertility (as mentioned previously). When we examined the TTP values

after ≤4 years (2–4 years) and >4 years (5–17 years) of infertility, we found a significant (p < 0.001) difference even in the case of physiological FLF in the first pregnancies: 3.69 ± 2.7 cycles and 2.83 ± 2.2 cycles. Nevertheless, this difference of

barely one cycle does not have actual clinical importance, and the yearly cumulative

pregnancy rates do not differ any more between the two groups in the first pregnancies (98.6 and 98.2).

Another universal observation is that pregnancy outcome worsens with age

(Adamson and Baker 2003; ESHRE 2005; Joseph et al. 2005; Balasch and Gratacós

2011; Thoma et al. 2013) regarding miscarriage, preterm birth, IUGR, foetal developmental disorders, etc. The rapid increase in the miscarriage rate is especially drastic:

the incidence saliently increases over 35 years of age (9 % in age between 20–24 and

75 % in age over 45 years, Balasch and Gratacós 2011). At the same time, we found

that pregnancy outcome is particularly favourable with physiological FLF. Every

manifestation of adverse pregnancy outcome occurs dramatically less often compared

not only to the untreated group but also to the national average (Table 6.4). We could

not demonstrate a difference in pregnancy outcomes in terms of age regarding patients

under 35 years and patients of at least 35 years of age (Chap. 7).

Pregnancy outcomes of spontaneous conception get less favourable in parallel

with the length of infertility, regardless of the patient’s age. Miscarriage, extrauterine pregnancy, preterm birth, IUGR, etc. all occur more frequently with the increase

of TTP (Ghazi et al. 1991; Guillaume et al. 1995; Guzick et al. 1998; Raatikainen

et al. 2012). The pregnancy outcomes in the untreated control group of our study

also strengthened these observations. Almost every form of adverse pregnancy outcome occurred in a significantly (p < 0.001) lower proportion with physiological

FLF – especially in the case of average luteal P levels over 23 ng/ml – than in the

untreated control group and the total national population as well (Table 6.4).

The unanimously accepted view in the literature is that the main cause of the

age-dependent deterioration of fertility and pregnancy outcomes is the ageing of the

ovarium and particularly the oocyte, which is proportional to the patient’s age

(ESHRE 2005; Balasch and Gratacós 2011). Our results contradict this concept.

Fertility and pregnancy outcomes became physiological with the normalisation of

FLF, regardless of age. The sole possible interpretation of this is that a reversible

functional disorder underlies these phenomena instead of an organic cause. This

issue has gained more importance in recent decades; people tend to postpone starting a family until later and later in life (especially in developed countries).

Our results prove without any doubt that FLI is the main cause of UI. By embracing this view, every phenomenon connecting with UI can be understood:

1. The chance of conception decreases with the increasing length of the infertile

period.

The longer the presence of insufficient FLF caused by stress and obesity, the

less likely spontaneous normalisation is. By normalising FLF, the fertility of

patients becomes physiological.

2. The chance of conception decreases with the increasing age of patients.



6.2



Discussion



115



Ovarian function declines in proportion to age – especially in over 35s – and

thus FLI becomes more frequent. The age-dependent alterations are compensated by physiological FLF and fertility returns to the physiological level.

3. Pregnancy outcomes grow less favourable with the length of infertility and the

age of the patients.

The longer FLI is present, or the more impaired FLF becomes with age, the

less chance there is for FLF to spontaneously normalise completely. Different

levels of FLI underlie the various forms of adverse pregnancy outcome. Severe

FLI (FLI grade III, P < 11 ng/ml) results in infertility. Medium FLI (FLI grade II,

P > 11 and <17 ng/ml) results in miscarriage. Mild FLI (FLE grade I, P > 17 and

<23 ng/ml) results in preterm birth, IUGR and preeclampsia.

4. There is a greater chance of conception in the case of secondary infertility (1.8×).

There is a greater chance of repeated normalisation if FLF spontaneously normalised at least partly (miscarriage, preterm birth) or completely (mature birth)

once than if this did not happen before. In other cases, insufficient FLF occurs

only later, after physiological conditions (mature birth). Most pregnancies in the

medical history of patients with secondary infertility ended in miscarriage.

The introduction of in vitro fertilization (IVF) (1978) was a major step forward

in the treatment of infertility. It provided successful treatment for patients whose

infertility could not be solved by any other therapeutic method (severe oligospermia, the absence or bilateral blockage of oviducts, failure of other methods), and not

surprisingly, it became used worldwide. While admitting its gap-filling role, it cannot be the exclusive therapeutic method for every infertile couple in its current

form. Over the 36 years that have passed since IVF was introduced, approximately

four million “test tube babies” have been born worldwide (Conrad and Baker 2013).

However, 72 million couples suffer from not having children at any given time

(Boivin et al. 2007). Based on this it can be concluded that IVF provides a solution

for only 1–2 % of the couples worldwide who struggle with the lack of children.

Besides, as it is expensive and often comes with obstetric complications, its general

application is quite limited. Therefore, the need still persists for more successful,

simple and widely applicable methods in cases in which they are possible.

IVF is becoming more widely generally used in the treatment of UI. From the

currently available UI therapies, IVF undoubtedly yields the best monthly pregnancy rate. With the combined application of gonadotropin stimulation and intrauterine insemination (IUI), similar pregnancy rates can be achieved over three

cycles than in the first cycle in IVF. Therefore, many authors recommend IVF only

if this combined method fails (Ray et al. 2012). By combining CC treatment and IUI

(ESHRE and ASRM 2012; Ray et al. 2012) together with ultrasound and singular P

control, some authors have achieved monthly pregnancy rates between 15 and 20 %

over 12 months in UI. Yet, because of the impatience of the patient (and the doctor),

IVF is increasingly used as the first choice for treating UI.

The method we have described seems appropriate for replacing IVF in UI, based

on the efficacy of the two methods. Data concerning the efficacy of IVF is based on

the publications of Barnhart (2013) and Maliza et al. (2013) who presented the data

for the year 2009 in the USA. National data from Hungary is not available.



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Unexplained Infertility and Folliculo-Luteal Function



1. When using IVF, the CPR over three cycles is 53.2 and 73.8 % over six cycles

(Malizia et al. 2013). The corresponding values achieved by our method are 64.1

and 82.5 %. Moreover, our treatment method can be continuously applied over

successive cycles, in contrast with IVF (which is usually performed in three

cycles per year), and thus pregnancies may occur within a significantly shorter

period. While our method results in conception in 98.4 % of cases over 1 year,

IVF results in only 53.2 %. IVF is also much more expensive.

2. It is an important factor that obstetrical complications occur significantly

more often in pregnancies conceived with IVF than in spontaneously conceived pregnancies. Preterm birth (33.4 and 12.2 %), extreme low birth weight

(<1,500 g) (6.1 and 2 %) and IUGR (32 and 8 %) occur almost three times

more frequently. Preeclampsia (odds ratio 1.5), developmental disorders

(odds ratio 1.3) and multiple pregnancy (29.8 %) are also more prevalent in

IVF (Barnhart 2013; Malizia et al. 2013). The incidence of these complications decreases with an order of magnitude with physiological FLF: preterm

birth, 0.7 %; IUGR, 0.7 %; preterm birth with extreme low weight, 0.17%;

preeclampsia, 0 %; and twin birth, 6.3 %.

Out of our patients, 42 underwent 2–7 unsuccessful IVF procedures in their medical history because of UI, and all of them successfully conceived with physiological FLF, with all pregnancies but one resulting in mature birth. Based on the above,

our therapeutic method seems to be the most successful treatment of UI, and additionally, it can be widely implemented as it is simple and low cost.



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