32 research outputs found
Is there a future for ovulation induction in the current era of assisted reproduction?
The clinical use of medical induction of ovulation in normogonadotrophic
anovulatory women (WHO II), including polycystic ovary syndrome, is
increasingly questioned. However, we believe that this treatment modality
still represents a highly effective means of fertility treatment in women
with low pregnancy chances without intervention. A conventional treatment
algorithm involving clomiphene citrate (CC) followed by FSH induction of
ovulation may result in a 71% cumulative singleton live birth rate. In
attempts to improve treatment outcome further and reduce complication
rates, new compounds such as insulin-sensitizing agents or aromatase
inhibitors are currently used increasingly. Approaches such as patient
selection for different treatment modalities on the basis of initial
screening characteristics and alternative protocols for FSH ovulation
induction may also be proposed to render treatment algorithms more patient
tailored and therefore improve overall outcomes. More research is needed
in this area, rather than referring these patients to assisted
reproduction prematurely. This may lead to a more individually tailored
approach for ovulation induction in a given patient, resulting in a
further improvement of the balance between chances for success versus
complications
Urinary follicle-stimulating hormone for normogonadotropic clomiphene-resistant anovulatory infertility: prospective, randomized comparison between low dose step-up and step-down dose regimens
A low dose step-up and step-down regimen for induction of ovulation using
urinary FSH was compared in a prospective randomized fashion in 37
normogonadotropic clomiphene-resistant oligo- or amenorrheic infertile
women. The objectives was to assess potential differences in duration of
treatment, ovarian stimulation (serum FSH levels), and response [serum
estradiol (E2) levels and number and size of follicles]. Monitoring (blood
sampling and transvaginal sonography) took place on the day of initiation
of treatment, the first day of ovarian response as assessed by ultrasound
(i.e. the first day a follicle > or = 10 mm could be recognized), the day
of hCG administration to induce ovulation, and 3 days thereafter. The
median duration of treatment in the low dose step-up group was 18 (range,
7-41) days compared to 9 (range, 4-16) days in the step-down group (P =
0.003), and the total numbers of ampules administered were 20 (range,
7-69) and 14 (range, 7-33), respectively (P = NS). Serum FSH levels from
the first day of sonographic ovarian response until the administration of
hCG were constant (median increase, 2%/day) in patients receiving the low
dose step-up protocol, but showed a decrease (median, 5%/day) in step-down
cycles (P < 0.001). Monofollicular growth, defined as not more than one
follicle 16 mm or larger on the day of hCG administration, was observed in
56% of low dose step-up and 88% of step-down cycles (P = 0.04). The
percentage of patients with normal range periovulatory E2 serum levels
(500-1500 pmol/L) was 33% in the low dose step-up group vs. 71% in the
step-down group (P = 0.03). We conclude that a step-down protocol for
gonadotropin induction of ovulation exhibits a more physiological, late
follicular phase FSH serum profile than a low dose step-up protocol. This
results in a shorter duration of treatment, a greater number of
monofollicular cycles, and more cycles with periovulatory E2 levels within
the normal range in the step-down protocol
Low levels of follicle-stimulating hormone receptor-activation inhibitors in serum and follicular fluid from normal controls and anovulatory patients with or without polycystic ovary syndrome
In patients with normogonadotropic anovulation, either with or without
polycystic ovary syndrome (PCOS), factors interfering with FSH action may
be involved in arrested follicle development. The aim of this study is to
assess whether factors inhibiting FSH receptor activation are elevated in
serum or follicular fluid from anovulatory patients, as compared with
regularly cycling women. For this purpose, a Chinese hamster ovary cell
line, stably transfected with the human FSH receptor, has been applied.
FSH-stimulated cAMP secretion in culture medium was measured in the
presence of serum or follicular fluid. Chinese hamster ovary cells were
stimulated with a fixed concentration of FSH (3 or 6 mIU/mL) to mimic FSH
levels in serum or follicular fluid. Samples were added in concentrations
ranging from 3-90% vol/vol to approach protein concentrations occurring in
serum or follicular fluid. In the presence of 10% vol/vol serum from
regularly cycling women (n = 8), FSH-stimulated cAMP production was
inhibited to 42 +/- 2% (mean +/- SEM of 2 experiments, each performed in
duplicate) of cAMP production in the absence of serum, whereas a similar
cAMP level (up to 38 +/- 4% of the serum-free level) was observed at
higher concentrations of serum (30-90% vol/vol). The inhibition of
FSH-stimulated cAMP production in the presence of serum samples from
normogonadotropic anovulatory patients, without (n = 13) or with (n = 16)
PCOS, was similar to controls. Follicular fluid samples (n = 57) obtained
during the follicular phase in 25 regularly cycling women and follicular
fluid samples (n = 25) from 5 PCOS patients were tested in a slightly
modified assay system. In the presence of 10 or 30% (vol/vol) follicular
fluid, FSH-stimulated cAMP levels were decreased to 68 +/- 2% and 55 +/-
2% (mean +/- SEM of a single experiment in triplicate) of the cAMP levels
in the absence of follicular fluid, respectively. There was no correlation
between the degree of cAMP inhibition and follicle size, steroid content
(androstenedione or estradiol concentrations), or menstrual cycle phase.
Furthermore, no differences in inhibition were found, comparing PCOS
follicles with size- and steroid content-matched follicles obtained during
the normal follicular phase. It is concluded that inhibition of FSH
receptor activation by proteins present in serum or follicular fluid is
constant (60 and 40%, respectively) and independent from the developmental
stage of the follicle, either during the normal follicular phase or in
patients with normogonadotropic anovulation. Inhibition of FSH recepto
Child development and quality of parenting in lesbian families: no psychosocial indications for a-priori withholding of infertility treatment. A systematic review
Among fertility centres, much discussion focuses on whether to withhold
infertility treatment from special patient groups (lesbians, prospective
single parent(s), prospective parent(s) of relatively advanced age, or
with severe diseases) because it is assumed that this is in the best
interest of the child. The present study aimed to establish whether there
is any empirical evidence for this assumption. A literature search was
made in PubMed/Medline and PsycINFO to identify studies that had assessed
psychological outcomes of children and quality of parenting after
infertility treatment. Eight studies met the following inclusion criteria:
published in an English-language peer-reviewed journal between 1978 and
2002, and focused on psychosocial child development and quality of
parenting after infer
Age-related differences in features associated with polycystic ovary syndrome in normogonadotrophic oligo-amenorrhoeic infertile women of reproductive years
OBJECTIVE: To assess the effect of age on clinical, endocrine and
sonographic features associated with polycystic ovary syndrome (PCOS) in
normogonadotrophic anovulatory infertile women of reproductive years
Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is the most common cause of anovulation
in women. Previous studies suggest that the pathogenesis of PCOS may
involve interrelated abnormalities of the insulin-like growth factor (IGF)
and ovarian steroidogenesis systems. We investigated this hypothesis in
fasting serum samples from 140 women with PCOS (age, 27.4 +/- 0.4 yr; body
mass index, 26.3 +/- 0.5 kg/m2; mean +/- SEM). IGF-related parameters were
also studied in a group of normoovulatory women (n = 26; age, 26 +/- 4 yr;
body mass index, 23.6 +/- 4.3 kg/m2). For the PCOS group, the mean
testosterone (T) level was 2.5 +/- 0.1 nmol/L, and it was significantly
correlated with LH (r = 0.41; P < 10(-6)), estrone (r = 0.33; P = 0.016),
estradiol (r = 0.18; P = 0.04), and androstenedione (AD; P < 10(-6)), but
not with dehydroepiandrosterone sulfate (P = 0.71), a marker of adrenal
steroidogenesis. T and AD were also related to total ovarian follicle
number and ovarian size, as previously found with normoovulatory women
(1). There were no differences between the PCOS subjects and the
normoovulatory group for total IGF-I, IGF-II, or IGF-binding protein-3
(IGFBP-3). However, IGFBP-1 levels were significantly decreased in the
PCOS group (1.0 +/- 0.2 vs. 7.3 +/- 1.1 ng/mL; P < 0.001) and were
inversely correlated with serum insulin levels (r = -0.50; P < 10(-8)).
Serum levels of free IGF-I (fIGF-I) were elevated (5.9 +/- 0.3 vs. 2.7 +/-
0.3 ng/mL; P < 0.001) in inverse relation with IGFBP-1 (r = -0.31; P =
0.046). Serum fIGF-I levels were related to total follicle number (r = -
0.35; P < 10(-4)) and to the ratio of sex hormone-binding globulin to T (r
= -0.23; P = 0.009). However, these relationships were not independent of
other variables. Despite the more than 2-fold elevation in fIGF-I levels,
significant relationships between fIGF-I and markers of ovarian
steroidogenesis (T, AD, estradiol, and estrone) could not be demonstrated.
In conclusion, although we confirmed correlations between LH and
hyperandrogenemia and have found abnormalities in the IGF system in a
large cohort of PCOS subjects, a direct relationship between
hyperandrogenism and the IGF system could not be shown. Previous studies
suggest that elevated LH and hyperinsulinemia lead to excess ovarian
androgen synthesis in PCOS and that the intraovarian IGF system is
important for normal follicle development and may be important in the
arrested state of follicle development in PCOS. However, the data
presented in this cross-sectional study suggest that insulin-related
changes in circulating IGFBP-1 and subsequent elevation of fIGF-I reflect
insulin resistance and have little enhancing effects on ovarian
steroidogenesis in this disorder
Predictors of patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility
The diagnostic criteria used to identify patients suffering from
polycystic ovary syndrome remain controversial. The present prospective
longitudinal follow-up study was designed to identify whether certain
criteria assessed during standardized initial screening could predict the
response to ovulation induction with clomiphene citrate (CC) in 201
patients presenting with oligomenorrhea or amenorrhea and infertility.
Serum FSH levels were within the normal range (1-10 IU/L), and all
patients underwent spontaneous or progestin-induced withdrawal bleeding.
Initial CC doses were 50 mg daily for 5 days starting on cycle day 3. In
the case of an absent response, doses were increased to 100 and 150 mg
daily in subsequent cycles. First ovulation with CC was used as the end
point. After a complete follow-up (in the case of a nonresponse, at least
3 treatment cycles with daily CC doses up to 150 mg), 156 patients (78%)
ovulated. The free androgen index (FAI = testosterone/sex hormone-binding
globulin ratio), body mass index (BMI), cycle history (oligomenorrhea vs.
amenorrhea), serum androgen (testosterone and/or androstenedione) levels,
and mean ovarian volume assessed by transvaginal sonography were all
significantly different (P < 0.01) in responders from those in
nonresponders. FAI was chosen to be the best predictor in univariate
analysis. The area under the receiver operating characteristics curve in a
multivariate prediction model including FAI, BMI, cycle history, and mean
ovarian volume was 0.82. Patients whose ovaries are less likely to respond
to stimulation by FSH due to CC treatment can be predicted on the basis of
initial screening characteristics, such as FAI, BMI, cycle history
(oligomenorrhea or amenorrhea), and mean ovarian volume. These
observations may add to ongoing discussion regarding etiological factors
involved in ovarian dysfunction in these patients and classification of
normogonadotropic anovulatory infertile women
Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility
The present prospective follow-up study was designed to identify whether
clinical, endocrine, or ultrasound characteristics assessed by
standardized initial screening of normogonadotropic oligo/amenorrheic
infertile patients could predict conception in 160 women who reached
ovulation after clomiphene citrate (CC) medication. Additional inclusion
criteria were total motile sperm count of the partner above 1 million and
a negative history for any tubal disease. Daily CC doses of 50 mg
(increasing up to 150 mg in case of absent ovarian response) from cycle
days 3-7 were used. First conception (defined as a positive urinary
pregnancy test) was the end point for this study. A cumulative conception
rate of 73% was reached within 9 CC-induced ovulatory cycles. Patients who
did conceive presented more frequently with lower age (P < 0.0001) and
amenorrhea (P < 0.05) upon initial screening. In a univariate analysis,
patients with elevated initial serum LH concentrations (>7.0 IU/L) had a
higher probability of conceiving (P < 0.01). In a multivariate analysis,
age and cycle history (oligomenorrhea vs. amenorrhea) were identified as
the only significant parameters for prediction of conception. These
observations suggest that there is more to be gained from CC ovulation
induction in younger women presenting with profound oligomenorrhea or
amenorrhea. Screening characteristics involved in the prediction of
ovulation after CC medication in normogonadotropic oligo/amenorrheic
patients (body weight and hyperandrogenemia, as shown previously) are
distinctly different from predictors of conception in ovulatory CC
patients (age and the severity of cycle abnormality). This disparity
suggests that the FSH threshold (magnitude of FSH required for stimulation
of ongoing follicle growth and ovulation) and oocyte quality (chances for
conception in ovulatory cycles) may be differentially regulated
High singleton live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility (WHO 2)
BACKGROUND: Medical induction of ovulation using clomiphene citrate (CC)
as first line and exogenous gonadotrophins as second line forms the
classical treatment algorithm in normogonadotrophic anovulatory
infertility. Because the chances of success following classical ovulation
induction are not well established, a shift in first-line therapy can be
observed towards alternative treatment. The study aim was to: (i) reliably
assess the probability of singleton live birth following classical
induction of ovulation; and (ii) construct a prediction model, based on
individual patient characteristics assessed upon standardized initial
screening, to help identify patients with poor chances of success.
METHODS: A total of 240 consecutive women visiting a specialist academic
fertility unit with a history of infertility, oligomenorrhoea or
amenorrhoea, and normal FSH and estradiol serum concentrations (WHO group
2) was prospectively followed. The women had not been previously treated
with ovulation-inducing agents. All patients commenced with CC. Patients
who did not ovulate within three treatment cycles of incremental daily
doses up to 150 mg for 5 consecutive days or ovulatory CC patients who did
not conceive within six cycles, subsequently underwent gonadotrophin
induction of ovulation applying a step-down dose regimen. The main outcome
measure was pregnancy resulting in singleton live birth. Cox regression
was used to construct a multivariable prediction model. RESULTS: Overall,
there were 134 pregnancies ending in a singleton live birth (56% of
women). The cumulative pregnancy rate after 12 and 24 months of follow-up
was 50% and 71% respectively. Polycystic ovary syndrome (PCOS) patients
(49%), clearly non-PCOS patients (13%) and the in-between group did not
differ in prognosis (P = 0.9). The multivariable Cox regression model
contained the woman's age, the insulin:glucose ratio and duration of
infertility. With a cut-off value of 30% for low chance, the model
predicted probabilities at 12 months lower than this cut-off for 25 out of
240 patients (10.4%). CONCLUSIONS: Classical ovulation induction produces
very good results in normogonadotrophic anovulatory infertility.
Alternative treatment options may not be indicated as first-line therapy
in these patients, except for subgroups with poor prognosis. These women
can be identified by older age, longer duration of infertility and higher
insulin:glucose ratio