Recombinant luteinizing hormone

supplementation in assisted
reproductive technology: a
systematic review
Carlo Alviggi, M.D., Ph.D.,a Alessandro Conforti, M.D.,a Sandro C. Esteves, M.D., Ph.D.,b
Claus Yding Andersen, D.M.Sc.,c Ernesto Bosch, M.D.,d Klaus Bu € hler, M.D.,e Anna Pia Ferraretti, M.D.,f
Giuseppe De Placido, M.D., Antonio Mollo, M.D., Ph.D., Robert Fischer, M.D.,g
a a

and Peter Humaidan, M.D., D.M.Sc.,h for the International Collaborative Group for the Study of r-hLH (iCOS-LH)
a
Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples,
Italy; b Androfert, Andrology and Human Reproduction Clinic, Sa ~o Paulo, Brazil; c Laboratory of Reproductive Biology,
University Hospital of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark; d Instituto
Valenciano de Infertilidad, Valencia, Spain; e Center for Gynecology, Endocrinology, and Reproductive Medicine, Ulm
and Stuttgart, Germany; f SISMER, Reproductive Medicine Unit, Bologna, Italy; g Fertility Centre Hamburg, Hamburg,
Germany; and h Fertility Clinic, Skive Regional Hospital, Skive, Denmark, and Faculty of Health, Aarhus University,
Aarhus, Denmark

Objective: To assess the role of recombinant human LH (r-hLH) supplementation in ovarian stimulation for ART in specific subgroups
of patients.
Design: Systematic review.
Setting: Centers for reproductive care.
Patient(s): Six populations were investigated: 1) women with a hyporesponse to recombinant human FSH (r-hFSH) monotherapy; 2)
women at an advanced reproductive age; 3) women cotreated with the use of a GnRH antagonist; 4) women with profoundly suppressed
LH levels after the administration of GnRH agonists; 5) normoresponder women to prevent ovarian hyperstimulation syndrome; and 6)
women with a ‘‘poor response’’ to ovarian stimulation, including those who met the European Society for Human Reproduction and
Embryology Bologna criteria.
Intervention(s): Systematic review.
Main Outcome Measure(s): Implantation rate, number of oocytes retrieved, live birth rate, ongoing pregnancy rate, fertilization rate,
and number of metaphase II oocytes.
Result(s): Recombinant hLH supplementation appears to be beneficial in two subgroups of patients: 1) women with adequate presti-
mulation ovarian reserve parameters and an unexpected hyporesponse to r-hFSH monotherapy; and 2) women 36–39 years of age.
Indeed, there is no evidence that r-hLH is beneficial in young (<35 y) normoresponders cotreated with the use of a GnRH antagonist.
The use of r-hLH supplementation in women with suppressed endogenous LH levels caused by GnRH analogues and in poor responders
remains controversial, whereas the use of r-hLH supplementation to prevent the development of ovarian hyperstimulation syndrome
warrants further investigation.
Conclusion(s): Recombinant hLH can be proposed for hyporesponders and women 36–39 years of age. (Fertil SterilÒ 2018;109:644–64.
Ó2018 by American Society for Reproductive Medicine.)
Key Words: Luteinizing hormone (LH), recombinant LH, ovarian stimulation, IVF/ICSI, ART
Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-
and-sterility/posts/28946-24532

Received June 17, 2017; revised December 8, 2017; accepted January 4, 2018.
C.A. reports personal fees from Merck outside the submitted work. A.C. reports personal fees from Merck outside the submitted work. S.C.E. reports per-
sonal fees from Merck and Besins outside the submitted work. C.Y.A. has nothing to disclose. E.B. reports personal fees as honoraria for speaking bu-
reaus and advisory boards from Ferring Pharmaceuticals, Merck Serono, MSD, Finox, TEVA, and Roche Diagnostics outside the submitted work. K.B.
reports personal fees from Merck and Stiftung Endometrioseforschung outside the submitted work. A.P.F. has nothing to disclose. G.D.P. has nothing
to disclose. A.M. has nothing to disclose. R.F. reports personal fees from Merck outside the submitted work. P.H. reports personal fees from Merck,
MSD, and IBSA and grants from Merck, MSD and Ferring outside the submitted work.
Reprint requests: Carlo Alviggi, M.D., Ph.D., Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II,
Naples, Italy (E-mail: alviggi@unina.it).

Fertility and Sterility® Vol. 109, No. 4, April 2018 0015-0282/$36.00

Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc.
https://doi.org/10.1016/j.fertnstert.2018.01.003

644 VOL. 109 NO. 4 / APRIL 2018


G
onadotropin therapy is pivotal in ovarian stimula-
tion. Its introduction in medical practice dates to
almost a century ago and represented a major
advance in infertility treatment (1). Whereas FSH is the
main regulator of antral follicular growth, LH plays key roles
in promoting steroidogenesis and in the development of the
leading follicle. Moreover, LH exerts different functions dur-
ing the different stages of both natural and stimulated cycles.
LH is a glycoprotein hormone synthesized by the anterior
pituitary gland under the stimulation of GnRH (2). It consists
of two noncovalent linked peptide subunits, a and b. The
three-dimensional structure and the active conformation of
the subunits are maintained by internal disulfide bonds (3).
Subunit a is identical in all gonadotropins, whereas subunit
b confers biologic specificity and has characteristic biologic
and immunologic properties (4). Separated peptide subunits
lack biologic activity. A heterodimeric protein binds to the
LH receptor and causes signal transduction. Glycosylation is
essential for the biologic function of LH and reflects a differ-
ential spectrum of bioactivities, and half-lives of LH isoforms
(5). The composition of LH isoforms, their longevity, and their
properties vary during the menstrual cycle and reproductive
life. For example, isoforms with a shorter half-life but higher
biopotency are more frequent in young women than in meno-
pausal women (6). During the menstrual cycle, the ratio of
biologic to immunologic activity slowly increases during
the follicular phase, peaks at midcycle, and decreases during
the luteal phase (5, 7). This pattern is greatly influenced by
the addition of a sialic acid (‘‘sialylation’’) or a sulfonic
group (‘‘sulfonation’’) to the terminal part of the
carbohydrate moieties of the LH b subunit. Specifically,
sialylation is associated with a prolonged half-life and sulfo-
nation accelerates hormone elimination (8). This change in
isoform profile seems to be essential for ovulation (9). LH
binds to the LH/hCG receptor (LHCG-R), which belongs to
the family of G protein–coupled receptors endowed with
seven transmembrane domains and a large N-terminal extra-
cellular domain. The intramolecular domain involves adenyl
cyclase via coupling to G proteins (10). LHCG-Rs are located
on ovarian theca, granulosa, and luteal cells. LHCG-R is
also present in extragonadal tissue (11) and may exert extra-
gonadal effects on implantation (12), regulation of oviduct
and cervical functions (13, 14), modulation of endometrial
angiogenesis and growth (15), brain development, and
sexual behavior (11). However, the physiologic significance
of these findings remains to be established (11).
Both FSH and LH exert crucial activity during folliculo-
genesis. The ‘‘two cell–two gonadotropin’’ model was long
the mainstay of our understanding of folliculogenesis (16).
According to this concept, LH stimulates theca cells thereby
advancing androgen production, and FSH governs the prolif-
eration of granulosa cells (GCs) and promotes E2 synthesis.
More recently, the two cell–two gonadotropin concept was
expanded with the finding that LH receptors are also ex-
pressed on GCs, especially after follicular selection, and their
expression is
10 times higher in the GCs of preovulatory fol-
licles than in antral follicles 3–10 mm in diameter (17). LH up-
regulates E2 output and aromatase CYP19 mRNA expression
(18, 19). Moreover, it cooperates with FSH in inducing local
VOL. 109 NO. 4 / APRIL 2018
Fertility and Sterility®
production of androgen, inhibin B, and growth factors (20).
Among these, insulin growth factors 1 and 2, which are
expressed in both GCs and theca cells throughout
folliculogenesis, are important promoters of follicular
maturation (21–23).
A large body of data on the use of exogenous LH supple-
mentation in controlled ovarian stimulation (OS) for assisted
reproductive technology (ART) has accumulated over the past
20 years. However, no clear picture emerges regarding the
clinical use of recombinant human LH (r-hLH) in OS for
ART. This could be related to the fact that previous meta-
analyses included different types of patients in the same
group, making it difficult to determine in which women LH
supplementation could be recommended (24, 25).
Consequently, to identify which women could benefit from
r-LH supplementation, we conducted a systematic review to
evaluate the efficacy of exogenous r-hLH in specific
subgroups of women undergoing ART.
MATERIALS AND METHODS
Search Strategy
We performed a systematic literature search in the Medline/
Pubmed and Scopus databases. The end date for these
searches was May 2017. The overall strategy for study identi-
fication and data extraction was based on the following key
words, alone or combined, ‘‘luteinizing hormone,’’ ‘‘recombi-
nant LH,’’ ‘‘rLH’’ ‘‘rhLH,’’ ‘‘ovulation induction,’’ ‘‘assisted
reproductive technology,’’ ‘‘ART,’’ ‘‘in vitro fertilization,’’
‘‘IVF,’’ ‘‘poor responders,’’ ‘‘hyporesponse’’ (Supplemental
Table 1; available online at www.fertstert.org). The reference
lists of relevant reviews and articles were hand searched.
Eligibility and Data Extraction
Eleven investigators with expertise in the field of reproductive
medicine examined randomized control trials (RCTs) in which
r-hFSH–alone protocols were compared with r-hFSH þ r-hLH
supplementation in the following in vitro fertilization (IVF)/
intracytoplasmic sperm injection (ICSI) populations: 1)
women with a hyporesponse to exogenous r-hFSH monother-
apy; 2) women at an advanced reproductive age (R35 y); 3)
women cotreated with the use of GnRH antagonist; 4) women
with profoundly suppressed LH levels after the administration
of GnRH agonists during OS; 5) normoresponder women to
prevent ovarian hyperstimulation syndrome (OHSS); and 6)
women with a poor response to OS, including those who
met the European Society of Human Reproduction and
Embryology (ESHRE) Bologna criteria (26). Hyporesponders
were defined as normogonadotropic women with a normal
ovarian reserve who required elevated doses of r-hFSH
(>2,500 IU) to achieve an adequate number of oocytes or
who had a steady response in terms of both follicular growth
and E2 level during OS.
Data extraction was performed independently by three
authors (C.A., A.C., and S.C.E.) with the use of predefined
data fields.
645
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
Outcome Measures
The following outcomes were evaluated: live birth rate,
ongoing pregnancy rate, pregnancy rate, implantation rate,
fertilization rate, number of oocytes retrieved, and number
of metaphase II (MII) oocytes.
Protocol
This study was exempted from Institutional Review Board
approval, because it did not involve any human intervention.
We adhered to the Preferred Reporting Items for Systematic
Reviews and Meta-analyses (PRISMA) guidelines (27).
Study Selection
All articles were initially screened by title and abstract. Duplica-
tions were removed with the use of Endnote online software and
manually. Disagreements were resolved by discussion. The full
texts of eligible articles published in English were subsequently
obtained. Only full-text articles written in English concerning
RCTs were included. The gray literature, namely, unpublished
studies and those published outside widely available journals, re-
ports, conference proceedings, doctoral theses/dissertations, etc.,
was not considered (28) (Supplemental Table 1).
FIGURE 1
Flow chart.
Alviggi. Recombinant LH in ART. Fertil Steril 2018.
646
Bias Assessment
Two authors (A.C. and C.A.) independently assessed the risk of
bias of the studies eligible for the review by means of the
checklist created by the Cochrane Menstrual Disorders and
Subfertility Group (24). The quality of allocation concealment
was graded as adequate (A), unclear (B), or inadequate (C).
RESULTS
Study Selection and Characteristics
A total of 5,907 items were identified in the Medline/Pubmed
(n ¼ 3,670) and Scopus (n ¼ 2,237) databases (Fig. 1). Only
one item (29) was identified from the analysis of reference
lists. Duplications were removed with the use of Endnote On-
line (n ¼ 368). Abstracts and titles (n ¼ 5,539) were reviewed
by three authors (C.A., S.C.E., and A.C.). Disagreements were
resolved by discussion among all authors. Forty full-text pa-
pers were assessed for eligibility. Ten studies were excluded
because they did not fulfill the inclusion criteria (30–39).
Thirty studies were identified and included in our review.
Characteristics of the studies and the risk of bias and
included are reported in Table 1 and Supplemental Table 2
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 TABLE 1
VOL. 109 NO. 4 / APRIL 2018

Characteristics of included studies.

Study Period of Pituitary Outcomes
Reference type observation Country suppression Population Intervention Comparison measured Results
Acevedo RCT NA Spain GnRH n ¼ 42; Group B: Group A: Fertilization rate Group A > B
et al. (single- antagonist: age 18–35 y; n ¼ 22; n ¼ 20; (83% vs. 71%;
2004 (40) center) cetrorelix donor cycle rFSHþrLH; rFSH P< .05)
(0.25 mg/d) rLH started MII oocytes Group A > B
on stimulation (80% vs. 71%;
day 6; P< .05)
rLH dosage Implantation rate Group A > B
75 IU/d (35% vs. 15%;
P< .05)
Clinical Group A z B
pregnancy (51% vs. 30%;
rate NS)
Barrentexea RCT January–June Spain GnRH short n ¼ 84; Group A: Group B: No. oocytes Group A z B
et al. 2008 2005 (single- agonist: age R40 y; n ¼ 42; n ¼ 42; retrieved (5.43  0.4 vs.
(41) center) leuprolide basal FSH rFSHþrLH; rFSH 5.66  0.5;
(0.5 mg) R10 mIU/mL rLH started on P¼ .84)
stimulation Implantation rate Group A z B
day 7; (8.12  2.8 vs.
rLH dosage 6.86  2.2;
150 IU/d P¼ .49)
Pregnancy rate Group A z B
per started (23.8% vs.
cycle 21.43%;
P¼ .44)
Berkkanoglu RCT NA Turkey GnRH short n ¼ 97; Group A: Group B: No. MII oocytes Group A z B
et al. 2007 (single- agonist: AFC <12; n ¼ 46; n ¼ 51; (4.8  0.6 vs. 5.6
(42) center) leuprolide age %42 y rFSHþrLH; rFSH  0.7; NS)
(40 mg); rLH started on Clinical Group A z B
OC before stimulation pregnancy (27.5% vs.
stimulation day 7; rate per 27.1%; NS)
rLH dosage transfer
75 IU/d
Bosch et al. RCT January 2005– Spain GnRH n ¼ 292; Group A: Group B: No. oocytes Group A z B
2011 (43) December (single- antagonist: age 36–39 y n ¼ 150; n ¼ 142; retrieved (8.4  4.5 vs.
2007 center) cetrorelix rFSHþrLH; rFSH 10.1  6.3;
(0.25 mg/d); rLH started on P¼ .08)
OC during the stimulation Fertilization rate Group A > B
cycle before day 1 (68.0% vs.
stimulation rLH dosage 61.2%;

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75 IU/d P¼ .03)
Implantation rate Group A > B
(OR 1.56, 95% CI
1.04–2.33;
P< .05)
Ongoing Group A z B
pregnancy (OR 1.49, 95% CI
rate 0.93–2.38;
647

NS)
Alviggi. Recombinant LH in ART. Fertil Steril 2018.
 TABLE 1
648

ORIGINAL ARTICLE: ASSISTED REPRODUCTION

Continued.
Study Period of Pituitary Outcomes
Reference type observation Country suppression Population Intervention Comparison measured Results
n ¼ 333; Group A: Group B: No. oocytes Group A z B
age %35 y n ¼ 161; n ¼ 172; retrieved (10.9  6.2 vs.
rFSHþrLH rFSH 11.3  6.2;
P¼ .18)
Fertilization rate Group A z B
(67.4% vs.
67.4%;
P¼ .99)
Implantation rate Group A z B
(OR 1.03, 95% CI
0.73–1.47;
NS)
Ongoing Group A z B
pregnancy (OR 1.00, 95% CI
rate per cycle 0.66–1.52;
NS)
Caserta et al. RCT 2005–April Italy GnRH long n ¼ 999; Group A: Group B: No. clinical OHSS Group A < B
2011 (44) 2010 (single- agonist: age %40 y n ¼ 498; n ¼ 501; (0.2% vs. 1.6%;
center) triptorelin rFSHþrLH; rFSH P< .05).
(0.1 mg) rLH started on No. interrupted Group A < B
stimulation day 7; for OHSS risk (2.4% vs. 8.3%;
rLH dosage 75 IU/d P< .000001)
Clinical Group A > B
pregnancy (16.8% vs.
rate 11.9%;
P< .05)
C
edrin-Durnerin RCT April 2002– France GnRH n ¼ 203; Group A: Group B: No. oocytes Group A z B
et al. June 2003 (multicenter) antagonist: age 19–38 y n ¼ 107; n ¼ 96; retrieved (9.9  4.7 vs. 9.8
2004 (45) cetrorelix rFSHþrLH; rFSH  4.7; NS)
(3 mg); rLH started Implantation rate Group A z B
OC during the with GnRH (19.1% vs.
cycle before antagonist; 17.4%; NS)
stimulation rLH dosage 75 IU/d Live birth rate per Group A z B
cycle (25.2% vs. 24%;
NS)
De Placido RCT February– Italy GnRH n ¼ 117; Group A: Group B: No. oocytes Group A > B
et al. December (multicenter) long age 18–37 y; n ¼ 59; n ¼ 58; retrieved (9.0  4.3 vs. 6.1
2005 (46) 2003 agonist: hyporesponse rFSHþrLH; rFSH step-up  2.6; P< .01)
triptorelin defined as E2 rLH started on No. MII oocytes Group A > B
VOL. 109 NO. 4 / APRIL 2018

(3.75 mg) <180 pg/mL stimulation day 8; (7.8  4.3 vs.

and R6 follicles rLH dosage 150 IU/d 4.7  1.6;
6–10 mm but no P< .01)
follicles >10 mm Ongoing Group A z B
on stimulation day 8 pregnancy (32.5% vs. 22%;
rate NS).
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 TABLE 1
VOL. 109 NO. 4 / APRIL 2018

Continued.
Study Period of Pituitary Outcomes
Reference type observation Country suppression Population Intervention Comparison measured Results
Fabregues RCT November Spain GnRH long n ¼ 120; Group A: Group B: No. oocytes Group A < B
et al. 2003– (single- agonist: age 35–42 y n ¼ 60; n ¼ 60; retrieved (6.3  0.7 vs. 7.9
2006 (47) September center) triptorelin rFSHþrLH; rFSH  0.7; P¼ .01)
2004 (0.1 mg/d) rLH started on No. MII oocytes Group A < B
stimulation day 6; (5.5  0.7 vs. 6.9
rLH dosage 150 IU/d  0.6; P¼ .01)
Implantation rate Group A z B
(20.6% vs.
21.7%; NS)
Clinical Group A z B
pregnancy (40% vs. 42%;
rate per cycle NS)
Fabregues RCT January 2007– Spain GnRH long n ¼ 187; Group A1: Group B: No. oocytes Groups A1 and
et al. February (single- agonist: age 35–41 y n ¼ 62; n ¼ 62; retrieved A2 < B
2011 (48) 2008 center) triptorelin rFSHþrLH. rFSH (6.2  2.5 group
(0.1 mg/d) Group A2: A1 and 6.0 
n ¼ 63; 3.5 group A2
rFSHþrLH. vs. 7.8  3.9
rLH started on group B;
stimulation day P¼ .02)
6 in A1 and A2; No. MII oocytes Groups A1 and
A1 rLH dosage A2 z B
37.5 IU/d; (5.8  1.5 group
A2 rLH dosage A1 and 5.1 
75 IU/d 2.1 group A2
vs. 6.8  2.1
group B; NS)
Implantation rate Groups A1 and
A2 z B
(15.2% group A1
and 16.5%
group A2 vs.
25% group B;
NS)
Clinical Groups A1 and
pregnancy A2 z B
rate per cycle (22.5% group A1
and 26.9%

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group A2 vs.
35.4% group
B; NS)
Alviggi. Recombinant LH in ART. Fertil Steril 2018.
649
 TABLE 1
650

ORIGINAL ARTICLE: ASSISTED REPRODUCTION

Continued.
Study Period of Pituitary Outcomes
Reference type observation Country suppression Population Intervention Comparison measured Results
F. Ramirez RCT January– Spain GnRH n ¼ 34; Group A: Group B: No. oocytes Group A z B
et al. June (single- antagonist: age %37 y; n ¼ 16; n ¼ 18; retrieved (4.5  2.6 vs. 5.8
2006 (29) 2006 center) cetrorelix risk of poor rFSHþrLH; rFSH  2.1; P¼ .19)
(0.25 mg/d) response rLH started with No. MII oocytes Group A z B
defined as GnRH antagonist; (3.1  2 vs. 3.3 
poor rLH dosage 150 IU/d 1.7; P¼ .32)
response Pregnancy rate Group A z B
in a previous per started (16.6% vs.
cycle (cancellation cycle 12.5%; NS)
due to inadequate
response) or basal
FSH R8.5 mIU/mL
Ferraretti RCT January Italy GnRH long n ¼ 104; Group A: Group B: No. oocytes Group A > B
et al. 2002– (single- agonist: age %37 y; n ¼ 54; n ¼ 50; retrieved (11.1 vs. 8.2;
2004 (49) April center) triptorelin hyporesponse rFSHþrLH; rFSH step-up P< .05)
2003 (3.75 mg) defined as rLH started from Pregnancy rate Group A > B
plateau in midfollicular per embryo (54% vs. 24.4%;
follicular growth phase; transfer P< .05)
in stimulation days rLH dosage Implantation rate Group A > B
7–10 in patients 75–150 IU/d (36.8% vs.
with >10 antral 14.1%;
follicles P< .05)
Ferraretti RCT 2008–2010 Italy GnRH n ¼ 43; Group A: Group B: No. oocytes Group A > B
et al. (single- agonist age %38 y; n ¼ 22; n ¼ 21 retrieved (3.5  1.7 vs. 2.4
2014 (50) center) poor response rFSHþrLH; rFSH  1; P< .05)
according to the rLH started 4 days Implantation rate Group A z B
Bologna criteria before rFSH; (29% vs. 6%;
rLH dosage 150 P¼ .06)
IU/d Live birth rate/ Group A > B
patient (32% vs. 5%;
P¼ .025)
Velasco RCT NA Spain GnRH n ¼ 51; Group A: Group B: No. oocytes Group A < B
et al. (single- antagonist: age 18–35 y n ¼ 26; n ¼ 25; retrieved (11.4  8.7 vs.
2007 (51) center) cetrorelix rFSHþrLH; rFSH 16.1  9.9;
(2 mg group LH started on P¼ .04)
A; 0.25 mg/d stimulation Implantation rate Group A z B
group B) day 6; (32.1% vs.
rLH dosage 375 IU/d 23.2%; NS)
Clinical Group A z B
VOL. 109 NO. 4 / APRIL 2018

pregnancy (46.1% vs.

rate per 40.0%; NS)
embryo
transfer
Alviggi. Recombinant LH in ART. Fertil Steril 2018.
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VOL. 109 NO. 4 / APRIL 2018

Continued.
Study Period of Pituitary Outcomes
Reference type observation Country suppression Population Intervention Comparison measured Results
Griesinger RCT June 2003– Germany GnRH antagonist: n ¼ 108; Group B: Group A: No. oocytes Group A z B
et al. May 2004 (single- cetrorelix age 20–39 y n ¼ 54; n ¼ 54; retrieved (426 vs. 416; NS)
2005 (52) center) (0.25 mg/d) rFSHþrLH; rFSH (total)
rLH started on Implantation rate Group A z B
stimulation day 2; (8.1% vs. 13.8%;
rFSH–rLH ratio 2:1 NS)
Clinical Group A z B
pregnancy (16.0% vs.
rate per 23.0%; NS)
embryo
transfer
Humaidan RCT November Denmark GnRH long n ¼ 231; Group A1 Group B1 Implantation rate Group A > B
et al. subgroup 2001– (single- agonist: age %40 y; n ¼ 21; n ¼ 18; (36.4% vs.
2004 (53) analysis October center) buserelin subgroup rFSH þrLH; rFSH 13.3%;
2002 (0.5 mg/d) analysis of rLH started on P< .05)
39 women with stimulation day 8; Clinical Group A1 z B1
age 35–40 y rFSH–rLH ratio 2:1 pregnancy (33.3% vs.
rate per cycle 22.2%; NS)
Subgroup analysis Group A2 (LH %1.20 Group B2 Implantation rate Group A2 z B2
of women divided IU/L): (LH %1.20 (30% vs. 32%;
into three groups n ¼ 40; IU/L): NS)
on the basis of day rFSHþrLH n ¼ 44; Clinical Group A2 z B2
8 LH levels (IU/L): rFSH pregnancy (40% vs. 34%;
%1.20, 1.21–1.98, rate per cycle NS)
and R1.99
Humaidan RCT January 2014– Denmark GnRH long n ¼ 939; Group A: Group B: No. oocytes Group A z B
et al. February (multicenter) agonist: age 18–41 y; n ¼ 462; n ¼ 477; retrieved (3.3  2.71 vs.
2017 (54) 2015 triptorelin BMI 18 31 kg/m2; rFSHþrLH; rFSH 3.6  2.82;
acetate poor response rLH started on P¼ .054)
(0.1 mg) according to the stimulation day 1; Implantation rate Group A z B
Bologna criteria rFSH–rLH ratio 2:1 (14.7% vs.
15.6%;
P¼ .67)
Live birth rate Group A z B
(10.6% vs.
11.7%;
P¼ .66)
Konig et al. RCT January 2004– Netherlands GnRH n ¼ 253; Group A: Group B: No. oocytes Group A z B

Fertility and Sterility®

2013 (55) September (multicenter) antagonist: age 35–43 y n ¼ 125; n ¼ 128; retrieved (10.2  6.1 vs.
2010 cetrorelix rFSHþrLH; rFSH 10.9  6.4;
(0.25 mg/d) rLH started on P¼ .38)
stimulation day 6; Implantation rate Group A z B
rLH dosage 150 IU/d (20.3% vs.
23.5%;
P¼ .84)
Ongoing Group A z B
pregnancy (21.6% vs.
651

rate 24.8%;
P¼ .76)
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652

ORIGINAL ARTICLE: ASSISTED REPRODUCTION

Continued.
Study Period of Pituitary Outcomes
Reference type observation Country suppression Population Intervention Comparison measured Results
Lahoud et al. RCT 2007–2009 Australia GnRH long n ¼ 100; Group A: Group B: No. oocytes Group A z B
2017 (56) (multicenter) agonist age 18–42 y; n ¼ 43; n ¼ 57; retrieved (12  6.3 vs. 11.6
LH day 6–day rFSH þrLH; rFSH  5.6; P¼ .74)
0 ratio %0.5 rLH started on Clinical Group A z
stimulation day 7; pregnancy Group B:
rLH dosage 75IU/d rate per (36.1% vs.
transfer 43.5%;
P¼ .51)
Live-birth rate per Group A z
transfer Group B:
(27.8% vs.
37.0%;
P¼ .39)
Levi Setti RCT NA Italy GnRH antagonist: n ¼ 40; Group A: Group B: No. oocytes Group A z B
et al. (single- cetrorelix age %37 y n ¼ 20; n ¼ 20; retrieved (9.9  2.6 vs. 9.2
2006 (57) center) (0.25 mg/d) rFSHþrLH; rFSH  2.9; NS)
rLH started with Implantation rate Group A z B
antagonist; (35.0% vs.
rLH dosage 75 IU/d 30.0%; NS)
Ongoing Group A z B
pregnancy (20.4% vs.
rate per cycle 16.7%; NS)
Lisi et al. RCT NA Italy GnRH long n ¼ 453; Group A1: Group B1: Implantation rate Group A1 > B1
2002 (58) (single- agonist: subgroup rFSHþrLH; rFSH (71.4% vs. 7.1%;
center) triptorelin analysis of 8 rLH started on P< .001)
(0.1 mg/d) hyporesponders, stimulation day 7;
defined as higher rLH dosage 75 IU/d
rFSH dosage
consumption
(>2,500 IU)
Subgroup analysis Group A2 (LH <1.0 Group B2 (LH Implantation rate Group A2 > B2
of 22 women mIU/mL): <1.0 (15.4% vs. 0.0%;
with LH <1.0 rFSHþrLH mIU/mL): P< .05)
mIU/mL after rFSH
down-regulation
Lisi et al. RCT NA Italy GnRH long n ¼ 428; Group A (LH <1.0 IU/L): Group B (LH Clinical Group A z B
2005 (59) subgroup (single- agonist: age not specified; n ¼ 21; <1.0 IU/L): pregnancy (38% vs. 17%;
analysis center) triptorelin subgroup analysis rFSHþrLH; n ¼ 35; rate NS)
(0.1 mg) of 56 women rLH started on rFSH alone
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with LH <1.0 stimulation day 7;

mIU/mL after rLH dosage 37.5–75
down-regulation IU/d
Marrs et al. RCT NA USA GnRH long n ¼ 431; Group A: Group B: Implantation rate Group A z B
2004 (60) subgroup (multicenter) agonist: age 18–40 y; n ¼ 65; n ¼ 56; (21.7% vs.
analysis leuprolide subgroup analysis rFSH þrLH; rFSH 15.7%; NS)
(0.5 mg/d) of 121 women rLH started on Clinical Group A > B
aged R35 y stimulation day 6; pregnancy (OR 3.13, 95% CI
rLH dosage 150 IU/d rate 1.23–7.97;
P< .03)
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Continued.
Study Period of Pituitary Outcomes
Reference type observation Country suppression Population Intervention Comparison measured Results
Matorras RCT January Spain GnRH long n ¼ 131; Group B: Group A: Implantation rate Group A > B
et al. 2005 to (single- agonist: age 35–39 y n ¼ 63; n ¼ 68; (18.1% vs.
2009 (61) November center) triptorelin rFSHþrLH; rFSH 11.3%;
2006 (0.1 mg/d) rLH started on P¼ .04)
stimulation day 6; Live birth rate per Group A > B
rLH dosage 150 IU/d started cycle (19.0% vs. 7.4%;
P¼ .04)
Musters RCT August Netherlands GnRH long n ¼ 244; Group A: Group B: No. oocytes Group A z B
et al. 2008– (single- agonist: age 35–41 y, n ¼ 116; n ¼ 128; retrieved (8.6 vs. 7.4; NS)
2012 (62) April 2010 center) triptorelin or age <35 rFSHþrLH; rFSH Ongoing Group A z B
y with basal rLH started on pregnancy (13% vs. 12%;
FSH >12 IU/mL stimulation day 5; rate NS)
rFSH–rLH ratio 2:1
Nyboe RCT August Denmark GnRH long n ¼ 526; Group A: Group B: No. oocytes Group A z B
Andersen subgroup 2003– Sweden agonist: subgroup analysis n ¼ 49; n ¼ 51; retrieved (8.5  5.9 vs. 9.3
et al. analysis November Norway nafarelin of 100 women rFSH þrLH; rFSH  4.2; P¼ .47)
2008 (63) 2004 Finland (200 mg aged >35 y rLH started on Implantation rate Group A z B
(multicenter) twice a day) stimulation day 6; (0.26  0.41 vs.
rLH dosage 150 IU/d 0.29  0.40;
P¼ .72)
Ongoing Group A z B
pregnancy (16.3% vs.
rate at 12th 33.3%;
week P¼ .06)
Pezzuto et al. RCT March Italy GnRH long n ¼ 80; Group A: Group B: Fertilization rate Group A > B
2010 (64) 2004– (single- agonist: age 20–29 y; n ¼ 40; n ¼ 40; (92% vs. 69%;
October center) leuprorelin LH <0.5 mIU/mL rFSHþrLH; rFSH P< .001)
2007 (0.1 mL/d) on stimulation rLH started on Clinical Group A > B
day 6 stimulation day 6; pregnancy (22% vs. 5%;
rLH dosage 75 IU/d rate per P< .05)
transfer
Ruvolo et al. RCT September Italy GnRH long n ¼ 42; Group A: Group B: Pregnancy rate Group A > B
2007 (65) 2004– (single- agonist: hyporesponse, n ¼ 24; n ¼ 18; (45.4% vs.
February center) buserelin defined as E2 <180 rFSHþrLH; rFSH 25.0%;
2005 (0.2 mL/d) pg/mL and R6 rLH started on P< .01)
follicles 6–10 mm stimulation day 8; Implantation rate Group A > B
but no follicles >12 rLH dosage 75–150 IU/d (15.6% vs.
mm on stimulation 12.5%;

Fertility and Sterility®

day 8, and previous P< .01)
stimulation with
>3,000 IU rFSH
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 TABLE 1
654

ORIGINAL ARTICLE: ASSISTED REPRODUCTION

Continued.
Study Period of Pituitary Outcomes
Reference type observation Country suppression Population Intervention Comparison measured Results
Sauer et al. RCT NA USA GnRH n ¼ 42; Group A: Group B: No. MII oocytes Group A z B
2004 (66) (single- antagonist: age 18–39 y n ¼ 21; n ¼ 21; (median (10.0 vs. 11.0;
center) cetrorelix rFSHþrLH; rFSH values) NS)
(3 mg); rLH started on Implantation rate Group A z B
OC during the stimulation day 7–10; (37.3% vs.
cycle before rLH dosage 150 IU/d 25.6%; NS)
stimulation Clinical Group A z B
pregnancy (47.6% vs.
rate 52.4%; NS)
Vuong et al. RCT October 2012– Vietnam GnRH antagonist: n ¼ 240; Group A: Group B: No. oocytes Group A z B
2015 (67) June 2014 (single- cetrorelix age R35 y n ¼ 120; n ¼ 120 retrieved (7 vs. 8; P¼ .52)
center) rFSHþrLH; rFSH (median
rLH started on values)
stimulation day 6; Implantation rate Group A z B
rLH dosage 75 IU/d (12.47  34.63
vs. 11.13 
20.42; P¼ .75)
Live birth rate Group A z B
(16.7% vs.
17.5%;
P¼ .86)
Younis et al. RCT April 2010– Israel GnRH antagonist: n ¼ 62; Group A: Group B: No. oocytes Group A z B
2016 (68) April 2013 (single- cetrorelix age 35–44 y; n ¼ 32; n ¼ 30; retrieved (6.2  4.3 vs. 6.0
center) (0.25 mg/d) previous poor rFSHþrLH; rFSH  3.4; P¼ .97)
response rLH started with No. MII oocytes Group A z B
according to antagonist; (5.0  3.6 vs. 4.2
the Bologna rFSH–rLH ratio 2:1  2.3; P¼ .66)
criteria Clinical Group A z B
pregnancy (10.7% vs. 7.4%;
P¼ .67)
Note: Continuous data are presented as mean  SD or median value when specified; categoric data are presented as percentage or odds ratio (OR). AFC ¼ antral follicle count; BMI ¼ body mass index; CI ¼ confidence interval; NA ¼ not available; NS ¼ not significant;
rFSH ¼ recombinant FSH; rLH: recombinant LH.
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 Fertility and Sterility®

(the latter available online at www.fertstert.org). The overall
findings are summarized in Table 2.
Recombinant LH Supplementation in Women with
a Hyporesponse to Exogenous FSH Monotherapy
Four studies evaluated the effect of r-hLH in women with a
hyporesponse to FSH monotherapy (46, 49, 58, 65).
Lisi et al. (58) conducted an RCT in which unselected
women were randomized after pituitary down-regulation to
receive or not receive r-hLH supplementation commencing
on stimulation day 7. Although there were no significant
overall differences in terms of number of oocytes retrieved,
implantation rate, or pregnancy rate between the two groups,
the implantation rate was higher in the r-hLH–supplemented
than in the r-hFSH–alone group in a post hoc analysis of
women who required >2500 IU/d during OS (n ¼ 8; P¼ .001).
Ferraretti et al. (49) enrolled 126 women aged %37 years
undergoing OS after pituitary desensitization for ART in a
single-center RCT. Hyporesponsiveness to r-hFSH was
defined as the presence of a normal antral follicle cohort
(>10 antral follicles R8 mm in diameter) at the beginning
of OS, but a plateau in follicular growth (between day 7 and
day 10 of the cycles), with no increase in E2 level or in follic-
ular size despite continuous r-hFSH administration, at a fixed
dose. When this condition was detected in the midfollicular
phase, patients were randomized to receive: 1) an increment
in the r-hFSH dose (maximum 450 IU/d; n ¼ 50); 2) an incre-
ment in the r-hFSH dose plus r-hLH supplementation with
r-hLH (75 IU/d or 150 IU/d; n ¼ 54); or 3) an increment in
the r-hFSH dose plus hMG (n ¼ 22). Fifty-four age-matched
women with normal responses to OS served as the control
group. The average number of oocytes retrieved was signifi-
cantly lower in hyporesponders treated with the r-hFSH
step-up regimen vs. the other two groups (8.2 vs. 11.1 in the
r-hLH group and 10.9 in the hMG group; P< .05). Pregnancy
rates per embryo transferred were significantly higher in the
group treated with the increased r-FSH dose plus r-hLH (22
out of 41, 54.4%) than in the patients receiving r-hFSH alone
(11 out of 45, 24.4%) and in those receiving r-hFSH plus hMG
(2 out of 18, 11%; P< .05). Live birth rates in the r-hLH
(40.7%) and control (37%) groups were twofold higher than
in the other two groups (22% and 18%, respectively),
although the difference was not statistically significant.
De Placido et al. (46) investigated the effect of r-hLH sup-
plementation in hyporesponders (age 18–37 years, basal FSH
%9 IU/L) in a multicenter RCT involving 229 IVF/ICSI cycles.
Hyporesponse was defined as a steady response to OS (as
above [49]). All included women were treated with the use
of the GnRH-agonist long protocol associated with r-hFSH
at a daily dose of 225 IU. Only women who on day 8 of stim-
ulation displayed low serum E2 levels (<180 pg/mL) and no
follicles >10 mm were randomized to receive either r-hLH
supplementation at a daily dose of 150 IU (n ¼ 59) or a 150
IU increase in the daily dose of r-hFSH (n ¼ 58; r-hFSH
‘‘step-up’’ protocol). An age- and body mass index (BMI)–
matched population of normal responders (i.e., in whom E2
levels tripled between stimulation days 5 and 8, and who
had more than four follicles >10 mm on stimulation day 8)
served as the control group (n ¼ 112). The number of oocytes

TABLE 2

Summary of recombinant luteinizing hormone supplementation in assisted reproductive technology according to population treated.
No. studies/ Dosage and timing
Population participants Intervention Comparison Effect or r-hLH
Hyporesponders 4/672 r-hFSH þ r-hLH r-hFSH Better number of oocytes 150 IU/d started on
retrieved and stimulation day 8
implantation rate (Ferraretti et al. 2004; de
Placido et al. 2005)
Advanced age (35–39 y) 4/578 r-hFSH þ r-hLH r-hFSH Better implantation rate Antagonist: 75 IU/
d started on
stimulation day 1
(Bosch et al. 2011);
Agonist: 150 IU/d
started on
stimulation day 6–8
(Humaidan et al. 2004;
Marrs et al. 2004;
Matorras et al. 2009).
Cotreatment with GnRH 10/1,689 r-hFSH þ r-hLH r-hFSH No difference Not evaluated
antagonist
Profoundly suppressed 5/332 r-hFSH þ r-hLH r-hFSH No difference Not evaluated
LH levels after GnRH
agonist
Prevention of OHSS 1/999 r-hFSH þ r-hLH r-hFSH Lower OHSS cases 75 IU/d started on
stimulation day 8
Poor responders 7/1,483 r-hFSHþr-hLH r-hFSH No difference Not evaluated
Note: OHSS ¼ ovarian hyperstimulation syndrome.
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ORIGINAL ARTICLE: ASSISTED REPRODUCTION
retrieved was significantly higher in patients who received
r-hLH supplementation (9.0  4.3) than in those receiving
the increased r-hFSH dosage (6.1  2.6; P< .01). Implantation
and ongoing pregnancy rates were similar in hyporesponders
treated with r-hLH and normal responders (14.2% and 32.5%
vs. 18.1% and 40.2%, respectively). Conversely, both param-
eters were significantly lower in hyporesponders treated with
step-up r-hFSH than in normal responders (10.5% and 22.0%
vs. 18.1% and 40.2%; P< .05).
Ruvolo et al. (65) performed an RCT to test whether r-hLH
could improve oocyte quality in women with a hyporesponse
profile. Women with a history of stimulation with elevated r-
hFSH doses (>3,000 IU) pretreated with the use of GnRH
agonist from day 21 of the previous cycle were randomized
to receive r-hFSH alone or r-hFSH þ r-hLH (75 IU or 150
IU) from day 8 after starting r-hFSH stimulation. The rates
of pregnancy (45.4% vs. 25.0%; P< .01) and implantation
(15.6% vs. 12.5%; P< .01) were significantly higher in the
r-hLH–supplemented group than in the control group.
In conclusion, based on the evidence available, r-hLH
supplementation appears to be beneficial in women with a
hyporesponse to FSH monotherapy and GnRH agonist–
induced pituitary down-regulation. In this scenario, 75–150
IU r-hLH can be started at the midfollicular phase in an
attempt to rescue the ongoing cycle or at stimulation day 1
in a subsequent cycle.
Recombinant LH in Women of Advanced
Reproductive Age
Six RCTs evaluated r-hLH supplementation in advanced-age
women using the GnRH agonist long protocol (47, 48, 53,
60, 61, 63), and four RCTs used a GnRH antagonist protocol
(43, 55, 67, 68).
Marrs et al. (60) examined the efficacy of r-hLH supple-
mentation started on stimulation day 6 in an RCT involving
431 patients undergoing long agonist down-regulated ICSI
cycles in 44 centers in the USA. Only women aged 18–40 years
with basal serum/plasma FSH levels in the normal range were
included. Women with a clinically significant systemic dis-
ease and more than two previous ICSI cycles were excluded.
In a subgroup analysis, a tendency toward a higher implanta-
tion rate was observed in patients aged R35 years receiving
r-hLH supplementation than in their counterparts receiving
r-hFSH alone (21.7% vs. 15.7%). On the other hand, the clin-
ical pregnancy rate was higher (36.3% vs. 19.6%) in the sub-
group aged R35 years (range 35–40 y) receiving r-hLH (odds
ratio [OR] 3.13, 95% confidence interval [CI] 1.23–7.97;
P< .03) than in women treated with r-hFSH alone.
Humaidan et al. (53) conducted a prospective RCT in 231
women undergoing IVF or ICSI. Participants were %40 years
of age with regular menses and baseline FSH <10 IU/L.
Whereas IVF outcome did not differ among women
<35 years of age (n ¼ 192), the implantation rate was signif-
icantly higher (P< .05) in women R35 years of age (n ¼ 39)
treated with r-hLH (r-hFSH–r-hLH ratio 2:1).
Fabregues et al. (47) evaluated the effects of r-hLH sup-
plementation in 120 women R35 years of age undergoing
OS with a fixed dose of r-hFSH plus r-hLH (150 IU) starting
656
on day 6 (n ¼ 60) or r-hFSH alone (n ¼ 60). The women
enrolled in this study were 35–42 years of age with BMIs of
19–28 kg/m2, without previous ovarian surgery, and FSH
levels <12 IU/L. There were no significant differences be-
tween the two groups in terms of cycle cancellation, number
and quality of embryos, implantation rate, or clinical preg-
nancy rate. Moreover, significantly fewer oocytes were
retrieved (6.3  0.7 vs. 7.9  0.7; P< .01) and fewer MII oo-
cytes (5.5  0.7 vs. 6.9  0.6; P< .01) were observed in the
supplemented group than in the nonsupplemented group.
Nyboe Andersen et al. (63) evaluated 526 patients under-
going IVF/ICSI cycles. Only women with a regular menstrual
cycle (21–35 days) and basal FSH level <10 IU/L were
enrolled. A subgroup of women aged R36 years (n ¼ 100)
was stimulated with the use of r-hFSH (225 IU/d) or r-hFSH
plus r-hLH (150 IU/d) from day 6. The authors found that
ongoing pregnancy rates were similar in the two groups. In
addition, no intergroup differences were found in terms of im-
plantation rate and mean number of oocytes aspirated.
Matorras et al. (61) compared the effect of r-hFSH (n ¼
68) versus r-hFSH plus r-hLH (n ¼ 63; 150 IU/d starting on
day 6) in women aged 3539 years undergoing ICSI after pi-
tuitary desensitization with the use of a GnRH agonist.
Neither the number of oocytes retrieved nor the quality of em-
bryos differed between the groups. However, both the implan-
tation rate (18.1% vs. 11.3%; P¼ .04) and live birth rate per
cycle (19.0% vs. 7.4%; P¼ .04) were significantly higher in
women supplemented with r-hLH than in the nonsupple-
mented women.
Fabregues et al. (48) carried out a prospective randomized
trial of 187 women aged 35–41 years with normal BMI (19.8–
27.6 kg/m2), normal ovaries, no previous ovarian surgery, and
basal FSH level %12 IU/L. Patients were divided into three
groups. The control group underwent OS with r-hFSH alone
(group B; n ¼ 62); the study group underwent OS with r-
hFSH þ r-hLH at a fixed dose of 37.5 IU/d (Group A1; n ¼
62) or 75 IU/d (Group A2; n ¼ 63); r-hLH supplementation
started in the two study groups on day 6 of FSH stimulation.
No significant differences were observed among the three
groups in terms of clinical pregnancy or implantation rate.
Conversely, a significantly higher number of oocytes were
retrieved in the nonsupplemented group (6.2  2.5 in group
A1 and 6.0  3.5 in group A2 vs. 7.8  3.9 in group B; P¼ .02).
In an RCT involving 720 women, Bosch et al. (43) found
that the addition of r-hLH versus no supplementation signif-
icantly increased the implantation rate (26.7% vs. 18.6%, OR
1.56, 95% CI 1.04–2.33; P< .05) in patients 36–39 years of age
undergoing OS (n ¼ 292). Patients received r-hLH supplemen-
tation (75 IU/d) from stimulation day 1 and were cotreated
with the use of a GnRH antagonist. All patients were pre-
treated with oral contraceptives (OCs) during the previous cy-
cle. Furthermore, a clinically relevant, though not statistically
significant, higher ongoing pregnancy rate was observed in
the r-hLH group versus the nonsupplemented group (33.5%
vs. 25.3%, OR 1.49, 95% CI 0.93–2.38).
Konig et al. (55) randomized 253 women aged 35–43 years
undergoing IVF/ICSI to receive either 225 IU r-hFSH or r-
hFSH þ 150 IUr-hLH in a GnRH antagonist protocol.
Intention-to-treat analysis showed that implantation rates
VOL. 109 NO. 4 / APRIL 2018

(23.5% with r-hFSH alone vs. 20.3% with r-hFSH þ r-hLH)
and ongoing pregnancy rates (24.8% vs. 21.6%) were similar
in the two groups. Unlike the Bosch et al. study (43), r-hLH
supplementation started on stimulation day 6 and OCs were
not administrated.
Vuong et al. (67) conducted an RCT involving 240 women
>34 years of age (BMI <28 kg/m2 and no more than three IVF
attempts) who received ovarian stimulation with r-hFSH
starting from cycle day 2 or 3 in a GnRH antagonist protocol.
On day 6, patients were randomized to continue r-hFSH stim-
ulation alone or to r-hLH supplementation in a 2:1 r-hFSH–r-
hLH ratio (150/75 IU/d). Live birth rates did not differ between
the groups (16.7% vs. 17.5%), nor were there differences in the
number of oocytes retrieved, implantation rate, miscarriage
rate, or clinical pregnancy rate.
Finally, Younis et al. (68) investigated whether r-hLH
supplementation in women aged 35–44 years influenced the
outcomes of OS in GnRH antagonist cycles. This RCT included
women with a poor response based on the ESHRE Bologna
criteria (26). Sixty-two women were randomized to receive
either 300 IU/d r-hFSH plus 150 IU/d r-hLH starting on the
same day as the GnRH antagonist administration or r-hFSH
(300 IU/d) monotherapy. An r-hFSH–r-hLH ratio of 2:1 was
used in the r-hLH–supplemented group. Despite a trend to-
ward lower FSH consumption in the r-hFSH þ r-hLH group,
Younis et al. did not find any differences in the number of oo-
cytes retrieved, the number of MII oocytes, implantation rate,
or clinical pregnancy rate.
The available evidence suggests that r-hLH exerts a benefi-
cial effect in terms of implantation rate in women aged
36–39 years, regardless of the pituitary suppression protocol.
Nonetheless, no effect in terms of pregnancy rate was observed.
No significant effect was observed in studies in which women
aged R40 years were included in the groups receiving an
agonist or an antagonist regimen (47, 48, 55, 63, 67, 68).
Recombinant LH in GnRH Antagonist Cycles
Ten RCTs (40, 43, 45, 51, 52, 55, 57, 66–68) investigated the
effects of r-hLH in GnRH antagonist cycles.
Acevedo et al. (40) stimulated 42 young egg donors with a
fixed dose of r-hFSH (225 IU/d) for 6 days, followed by
randomization to continue stimulation with r-hFSH or with
r-hFSH plus 75 IU/r-hLHd. Significant differences were found
in the percentage of MII oocytes (80% vs. 71%; P< .05), two-
pronuclear zygote fertilization rate (83% vs. 71%; P< .05),
and embryo quality in favor of the group of donors who
received GnRH antagonist plus r-hLH. Similarly, implanta-
tion rates (35% vs. 15%; P< .05) were higher in recipients
who received embryos from donors treated with r-hLH.
Cedrin-Durnerin et al. (45) assessed the effect of r-hLH
supplementation in women 19–38 years of age with normal
ovarian function and BMI <30 kg/m2. Patients with a history
of a low (<5 oocytes) or high (>15 oocytes) response were
excluded. A total of 203 women was randomized to LH sup-
plementation (75 IU/d; n ¼ 107) or no supplementation
(n ¼ 96). No differences were observed between the groups
in terms of number of oocytes, number of embryos collected,
delivery rate per cycle, or implantation rate.
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Fertility and Sterility®
Sauer et al. (66) analyzed 65 women aged 18–39 years
who were randomized into three groups. Group 1 received
r-hFSH alone in a GnRH agonist protocol (n ¼ 23), group 2
received r-hFSH in a GnRH antagonist protocol with 3 mg ce-
trorelix (n ¼ 21), and group 3 was treated as group 2 was
except for the addition of 150 IU/d r-hLH from stimulation
day 7 to 10 (n ¼ 21). No differences were observed between
groups 2 and 3 in terms of number of MII oocytes, implanta-
tion rate per embryo transfer, or clinical pregnancy rate.
Griesinger et al. (52) analyzed 108 women aged 20–
39 years with regular menses. Women with a history of
more than three previous unsuccessful ART or OHSS proced-
ures were excluded. All women underwent OS with GnRH
antagonist cotreatment. Patients were randomized to receive
a r-hFSH (n ¼ 54) or r-hFSH plus r-hLH (n ¼ 54). Except for
higher E2 levels in the r-hLH group, no differences were re-
ported in terms of number of oocytes retrieved, implantation
rate, or clinical pregnancy rate between the groups.
Levi Setti et al. (57) enrolled women %37 years of age
with regular menses (25–35 d), normal BMI (<25 kg/m2),
and basal FSH <12 IU/mL. Patients with previous pelvic sur-
gery or endometriomas detected by means of ultrasound were
excluded. The patients were randomized to receive r-hFSH þ
r-hLH (n ¼ 20) or r-hFSH alone (n ¼ 20). No differences were
observed between the two groups regarding the number of MII
oocytes retrieved, implantation rate or pregnancy rate.
Garcia Velasco et al. (51) performed an open-label RCT
of 51 patients aged 18–35 years undergoing their first IVF
attempt. Women with a history of pelvic endometriosis,
polycystic ovarian syndrome, thyroid dysfunction, or gross
uterine or ovarian alterations found by means of transvagi-
nal ultrasound were excluded. The study group (n ¼ 26)
received r-hLH supplementation (375 IU/d) from stimulation
day 6 onward and high GnRH antagonist dosages (2 mg/d ce-
trorelix). The control group (n ¼ 25) received r-hFSH alone
and low GnRH antagonist doses (0.25 mg/d cetrorelix). Im-
plantation and clinical pregnancy rates per transfer were
similar in the study and control groups. A lower number
of oocytes retrieved was observed in the study group
compared with the control group (11.4  8.7 vs. 16.1 
9.9; P¼ .04).
The results of the studies by Bosch et al., Konig et al.,
Vuong et al., and Younis et al. (43, 55, 67, 68) concerning
the effect of r-hLH in older patients (>35 years old) treated
with the use of GnRH antagonists are reported in the
previous section. In the subgroup of women aged
%35 years (n ¼ 333), Bosch et al. (43) did not detect any
difference in fertilization rate, implantation rate, or ongoing
pregnancy rate between women stimulated with r-hFSH þ
r-hLH and those stimulated with r-hFSH alone.
The evidence concerning the clinical use of r-hLH in
GnRH antagonist cycles is limited to women 35–39 years
of age. In these women, a dosage of 75 IU r-hLH started
on the first day of OS significantly improved the implanta-
tion rate (43). No effect was detected in studies that included
women R40 years of age (55, 67, 68). Of note, although r-
hLH did not exert a beneficial effect in infertile women
<35 years of age undergoing IVF/ICSI (51, 52, 57, 66), it
improved the implantation rate and embryo quality in
657
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
donor cycles from young good-prognosis women without
infertility history (40).
Recombinant LH Supplementation in Women with
Severely Suppressed LH Levels after Long
GnRH-Agonist Down-Regulation
Five RCTs (53, 56, 58, 59, 64) investigated the role of r-hLH
supplementation in women with severely suppressed LH
levels due to GnRH agonist pituitary suppression.
Lisi et al. (58), in a subgroup analysis of women (n ¼ 22)
in whom LH was profoundly suppressed after agonist sup-
pression (defined as <1.0 mIU/mL at down-regulation confir-
mation), found a better implantation rate in women
supplemented with the use of r-hLH than in women receiving
the r-hFSH–alone regimen (15.4% vs. 0.0%; P< .05).
Humaidan et al. (53) divided down-regulated women
subjected to OS with r-hFSH into three subgroups based
on their endogenous LH concentration on stimulation day
8. Group 1 was constituted by women with LH levels
%1.20 IU/L (n ¼ 84), group 2 by women with LH levels
of 1.21–1.98 IU/L (n ¼ 73), and group 3 by women with
LH levels R1.99 IU/L (n ¼ 74). On day 8 of stimulation,
the patients in each subgroup were randomized to continue
stimulation with the use of r-hFSH alone or to add r-hLH to
the stimulation regimen with r-hFSH (2:1 ratio of FSH to
LH). Neither pregnancy rate nor implantation rate was
reduced in nonsupplemented women with LH levels %1.98
IU/L. The group of nonsupplemented women with LH levels
of R1.99 IU/L on day 8 had the lowest implantation rate.
Interestingly, LH supplementation in the latter group re-
sulted in increased implantation rate, an effect that was
not observed in the other two groups.
Lisi et al. (59) evaluated 428 women randomized to
receive r-hFSH alone, r-hFSH þ r-hLH (37.5 IU/d), or r-
hFSH þ r-hLH (75 IU/d). A subgroup analysis (n ¼ 56) re-
vealed that pregnancy rates were not lower in women with
low basal LH levels (<1.0 IU/L) than in women who main-
tained normal LH levels after GnRH agonist down-
regulation. Furthermore, the clinical pregnancy rate did not
differ between the r-hLH–supplemented group and the non-
supplemented group (38% vs. 17%; P>.05).
Pezzuto et al. (64) conducted a study involving 80 women
with suppressed LH levels (<0.5 mIU/mL) on stimulation day
6 after down-regulation with the use of leuprorelin and OS
with the use of r-hFSH monotherapy. The patients were ran-
domized to receive 75 IU/d r-hLH þ 225–300 IU r-hFSH (n ¼
40) or 225–300 IU r-hFSH alone (n ¼ 40). There were no sig-
nificant differences in the number of retrieved oocytes and
MII oocytes between the groups, but the clinical pregnancy
rates were higher in the group of patients supplemented
with r-hLH than in the group treated with r-hFSH alone
(22% vs. 5%; P< .05). Moreover, the fertilization rate was
higher in the group supplemented with r-hLH than in the
group treated with r-hFSH alone (92% vs. 69%; P< .001).
Lahoud et al. (56) carried out a multicenter RCT in which
100 women who had a R50% reduction in LH levels were
randomized to receive either r-hFSH plus rLH (n ¼ 43) or
r-hFSH alone (n ¼ 57). In the first group, r-hLH was admin-
658
istrated at a dosage of 75 IU/d from stimulation day 7. No
differences in live birth rate (27.8% vs. 37.0%, relative risk
[RR] 0.75, 95% CI 0.39–1.44) or clinical pregnancy rate per
embryo transfer (36.1% vs. 43.5%, RR 0.84, 95% CI 0.5–
1.48) were observed between the groups.
In conclusion, the existing evidence does not support the
use of LH supplementation in women with profound suppres-
sion of endogenous LH after GnRH agonist pituitary suppres-
sion. Larger trials are required to investigate more robust
outcomes, such as live birth rate. Such trials should be stan-
dardized regarding LH measurement frequency and definition
of LH suppression.
Recombinant LH in the Prevention of Ovarian
Hyperstimulation Syndrome
Only one RCT has assessed the effect of r-hLH supplementa-
tion on OHSS development (44).
Caserta et al. (44) investigated 999 infertile women
%40 years of age with basal FSH levels %12 mIU/mL and
no history of OHSS or polycystic ovary syndrome. The women
were randomized to receive r-hFSH alone (n ¼ 501) or r-hFSH
þ r-hLH (n ¼ 498). A daily dose of 150 IU r-hFSH was admin-
istered in both groups; r-hLH supplementation was given at a
dose of 75 IU/d from stimulation day 7 onward. No differ-
ences in age or mean number of embryos transferred were
observed between groups. Although the number of eggs
retrieved was lower in the supplemented group than in the
r-hFSH–alone group (6.1  3 vs. 6.6  3.8; P< .05), the clin-
ical pregnancy rate was higher in the supplemented group
than in the r-FSH–alone group (16.8% vs. 11.9%; P< .05).
The proportion of cancelled cycles owing to OHSS risk
(8.3% vs. 2.4%; P< .000001) and the proportion of patients
who developed clinical OHSS (1.6% vs. 0.2%; P< .05) were
significantly higher in the r-hFSH–alone group than in the
r-hFSH þ r-hLH group.
The Role of Recombinant LH Supplementation in
Women Classified as Poor Responders to Ovarian
Stimulation
Seven RCTs investigated the effect of r-hLH in poor re-
sponders (29, 41, 42, 50, 54, 62, 68). The definition of poor
responder was heterogeneous in four trials (29, 41, 42, 62),
and the ESHRE Bologna criteria (26) were adopted in the
remaining three studies (50, 54, 68).
Fernandez Ramirez et al. (29) investigated the effect of r-
hLH supplementation in women aged %37 years who were
classified as ‘‘poor responders’’ when at least one of the
following criteria was met: 1) presence of one of the following
events during a previous cycle: %3 preovulatory follicles at
hCG day or at cycle cancellation, %2 MII oocytes, or E2
%600 pg/mL at hCG day or at cycle cancellation; 2) cancella-
tion of a previous cycle owing to inadequate response to go-
nadotropins; or 3) baseline serum FSH R8.5 mIU/mL (day 2–5
of follicular phase). Thirty-four women were randomized into
two groups. Group 1 (n ¼ 18) was stimulated with the use of r-
hFSH monotherapy and group 2 (n ¼ 16) with r-hFSH þ r-
hLH (150 IU/d); r-hLH was started concomitantly with
VOL. 109 NO. 4 / APRIL 2018

GnRH antagonist administration. No significant differences
were observed regarding number of oocytes collected, number
of MII oocytes, and fertilization rate. Similarly, pregnancy
rates did not differ between groups.
Berkkanooglu et al. (42) studied 145 poor-responder pa-
tients, defined as having <12 antral follicles. All patients
were treated with the use of a microdose GnRH agonist proto-
col. Patients were randomized into three groups: Group A
(n ¼ 51) received r-hFSH alone; group B (n ¼ 46) received
r-hFSH þ r-hLH (75 IU/d); and group C (n ¼ 48) was stimu-
lated with r-hFSH þ hCG (75 IU/d). The clinical pregnancy
rates were similar in the three groups (27.1%, 27.5%, and
21.8% for groups A, B, and C, respectively). Furthermore, no
differences were detected in the number of MII oocytes
retrieved.
Barrenetxea et al. (41) studied the effect of r-hFSH versus
r-hFSH þ r-hLH in 84 poor-responder women. This popula-
tion was constituted by women >39 years of age with a day
3 baseline FSH level R10 mIU/mL undergoing their first stim-
ulation cycle. The authors found no differences between the
two groups in pregnancy rate, pregnancy rate per oocyte
retrieved, miscarriage rate, or implantation rate.
Musters et al. (62) performed an RCT in expected poor re-
sponders with the following characteristics: 1) age 35–
41 years; 2) basal FSH >12 IU/mL; and 3) antral follicle count
%5. A total of 244 women were randomized into two groups:
116 women were allocated to a stimulation regimen with r-
hFSH þ r-hLH, and 128 received r-hFSH alone. The ongoing
pregnancy rates and numbers of oocytes retrieved were
similar in the two groups.
Ferraretti et al. (50) studied the effect of r-hLH pretreat-
ment in poor-responder patients classified according to the
ESHRE Bologna criteria (26). The study group was constituted
by women in whom 150 IU/d r-hLH was administered for
4 days before stimulation with the use of 400 IU/d r-hFSH
(study group; n ¼ 22). The authors compared the IVF out-
comes of the study group with those of a group of women
(control group; n ¼ 21) stimulated without r-hLH pretreat-
ment and subjected to down-regulation with the use of either
a GnRH agonist (n ¼ 17) or a GnRH antagonist (n ¼ 4). The
number of oocytes retrieved (3.5  1.7 vs. 2.4  1; P< .05)
and live birth rate (32% vs. 5%; P¼ .025) were significantly
higher in the study group than in the control group.
Along the same lines, Younis et al. (68) studied the effect
of r-hLH supplementation in poor-responder women aged
35–44 years classified according to the ESHRE Bologna
criteria. As reported above (‘‘Efficacy of recombinant LH in
women at advanced reproductive age’’), the authors did not
find any differences in any of the outcome measures
evaluated.
In the largest multicenter RCT conducted thus far to
explore the use of r-hLH in poor ovarian responder patients
aligned with the Bologna criteria, Humaidan et al. (54) ran-
domized 939 women to undergo OS with r-hFSH plus r-hLH
(300 IU þ 150 IU) from day 1 of stimulation or only r-hFSH
(300 IU monotherapy). All women underwent long GnRH
agonist down-regulation. The primary end point was the
number of oocytes retrieved per patient. Overall, no differ-
ences were observed between groups regarding the primary
VOL. 109 NO. 4 / APRIL 2018
Fertility and Sterility®
end point, implantation rate, or live birth rate. A post hoc
analysis was performed with the use of a specific baseline
severity score (BSC). This score was based on the following
poor ovarian response (POR) inclusion criteria: age
R40 years and reduced ovarian reserve using stricter cutoffs
than those used in the trial, either <2 oocytes retrieved during
the most recent previous ART cycle or, if no previous cycle
data were available, baseline serum antim€ ullerian hormone
(AMH) level <0.5 ng/mL. The BSC was defined as ‘‘mild’’ if
none of these criteria were met, ‘‘moderate’’ if one criterion
was met, and ‘‘severe’’ if two criteria were met. Women with
moderate or severe BSC had a higher live birth rate when sup-
plemented with r-hLH than when treated with r-hFSH alone
(moderate BSC: 11% vs. 7.5% [P< .05]; severe BSC 9.6% vs.
4.5% [P< .05]), Conversely, women with a mild BSC had a
higher live birth rate when stimulated with r-hFSH alone
than when supplemented with r-hLH (10.6% vs. 32.7%;
P< .05).
Collectively, the evidence concerning the clinical effect of
r-hLH supplementation in poor-responder patients is incon-
clusive, mainly because of the high heterogeneity among tri-
als. Only one study with a small sample size reported that
supplementation of r-hLH before stimulation improved the
live birth rate per patient (50). Thus, r-hLH supplementation
in these women is not supported by the evidence currently
available.
DISCUSSION
This review summarizes evidence about the efficacy of r-hLH
supplementation in specific populations of normogonado-
tropic women undergoing OS in ART cycles. The use of r-
hLH in women with a hyporesponse to exogenous r-hFSH
was first reported in a series of studies conducted in Italy
(33, 46, 49, 58). These normo-ovulatory and normogonado-
tropic women differ from classical poor responders in the
sense that they are usually younger and have a normal age-
matched ovarian reserve. The term ‘‘hyporesponse’’ is used
to describe a condition of hyposensitivity or ovarian resis-
tance to standard age- and BMI-matched doses of exogenous
FSH (69, 70). This ovarian resistance may be clinically evident
in the form of an ‘‘initial slow response’’ or ‘‘stagnation’’ in
follicle growth, which, in turn, leads to higher FSH doses
and/or the need to supplement LH during OS. In other cases,
a hyporesponse is retrospectively diagnosed in women who
require higher than expected—on the basis of age, BMI, and
ovarian reserve—doses of gonadotropins. Notably, a
hyporesponse differs from a poor response in at least two
aspects. First, in hyporesponders, an adequate number of
oocytes is recruited, though at the expense of elevated
gonadotropin consumption, whereas in poor responders, the
number of oocytes retrieved is usually low regardless of the
amount of gonadotropin administered. Second, hypo-
responders have normal ovarian reserve tests (i.e., AMH and
antral follicle count), which are usually deranged in women
with POR.
With the definition of hyporesponse in mind, current evi-
dence indicates that in hyporesponders: 1) r-hLH supplementa-
tion starting from day 7–10 of OS can rescue the ongoing cycle,
659
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
thereby compensating for an initial slow response (stagnation)
(46, 49); 2) administration of r-hLH is more efficient than
increasing the dosage of r-hFSH; and 3) when a hyporesponse
is retrospectively identified (i.e., history of excessive
consumption of FSH), r-hLH supplementation from day 7 or 8
of stimulation seems to improve the outcome of IVF (58, 65).
Furthermore, it seems that 150 IU r-hLH results in more
oocytes retrieved and a higher percentage of mature oocytes
than does 75 IU r-hLH in a long GnRH agonist protocol (33).
All of these findings were obtained with the use of a GnRH
agonist long protocol. In contrast, the effect of r-hLH
supplementation in hyporesponders undergoing OS with the
use of GnRH antagonists remains to be established. The
mechanism by which r-hLH exerts its beneficial effect in
hyporesponders is not fully understood. It is plausible that an
excessively profound suppression of endogenous LH after
down-regulation with the use of GnRH analogues may create
the need for exogenous LH supplementation. However, neither
Ferraretti et al. (49) nor de Placido et al. (46) found a significant
association between serum LH levels during OS and the response
to r-hLH supplementation. This result led to the hypothesis that
the genetically determined characteristics of gonadotropins
and/or their receptors could be implicated in the pathogenesis
of hyporesponse (71–73). In particular, carriers of the Ser
variant had impaired FSH receptor sensitivity to exogenous
gonadotropins. Moreover, hyporesponsiveness to r-hFSH
seems to be, at least in part, related to the presence of a
polymorphism of the b chain of LH (74, 75). It is therefore
possible that in women with genetic polymorphisms
involving the gonadotropins and their receptors, LH
supplementation may overcome the genetically determined
ovarian resistance to gonadotropin stimulation. This
hypothesis should be verified in specific trials and could
represent an interesting target for future research.
Regarding the use of r-hLH in women of advanced age,
the present review indicates that: 1) r-hLH has a beneficial
effect on implantation and pregnancy rates in women
aged 36–39 years undergoing OS; and 2) the latter effect
is best documented in the large RCT conducted by Bosch
et al. with the use of GnRH antagonist regimen (43). Con-
trasting findings between Bosch et al. and others (55, 67,
68) could be explained in part by the ages of the women
enrolled in these studies: Whereas Bosch et al. (43)
enrolled only women aged 36–39 years, the other trials
(55, 67, 68) included women aged >39 years, in whom
dramatically elevated aneuploidy rates and a low ovarian
reserve is generally observed (76). In addition, the timing
of r-hLH administration and pretreatment with the use of
OCs might have contributed to differences among the
trials, because r-hLH supplementation administered at the
beginning of stimulation (43) seems to be more effective
than later administration in women cotreated in an
antagonist regimen (55, 67). The evidence that r-hLH
supplementation could be useful in advanced-age women
was confirmed in women undergoing a long GnRH agonist
down-regulation protocol. Specifically, a positive effect
was observed in an RCT of women 35–39 years of age
(61) and in a post hoc subgroup analyses of two RCTs
involving women 35–40 years of age (53, 60). Contrary to
660
what was observed with the use of an antagonist regimen,
after GnRH agonist pituitary suppression, the r-LH starting
dose seemed to be effective from 6 day of stimulation (61).
Interestingly, a premature increase in progesterone
associated with impaired IVF success (77) was more
frequently observed in r-hFSH–alone than in r-hFSH þ r-
hLH women, especially those of advanced age (43, 67, 68).
This finding suggests that r-hLH supplementation had a
beneficial effect in those women.
The positive effects of r-hLH in women of an advanced
age seem to be multifactorial. In particular, addition of exog-
enous LH might increase androgen production, which de-
creases in advanced age (78). Importantly, it was
demonstrated that r-hFSH administration alone is not able
to restore reduced age-related androstenedione synthesis
(79). Added to this, LH counteracts the age-related increase
in the apoptosis rate of GCs (65). LH up-regulates fibroblast
growth factor 2, amphiregulin, and epiregulin, which are
among the most crucial factors for angiogenesis and are
located in theca and GCs (80–82). Finally, recent studies
suggest that endometrial LH receptors could modulate the
embryo-endometrium crosstalk during implantation (83).
This effect could partially explain the higher implantation
rate observed in women of an advanced age supplemented
with the use of exogenous LH. In contrast, there is no evidence
that r-hLH supplementation is beneficial in young women,
regardless of the GnRH analogue regimen used (25, 84).
Notably, a single small RCT conducted in egg donors
cotreated with the use of GnRH antagonist suggested a
positive effect of r-hLH supplementation in young women
with no infertility history (40). Given the lack of other
robust studies, it remains to be seen whether r-hLH
supplementation could be of use in donor cycles.
Profound suppression of LH levels as a result of GnRH
agonist down-regulation has been reported in 7%–48% of
normogonadotropic women undergoing OS (85–88). Some
authors reported impaired ART outcomes (i.e., early
pregnancy loss, reduced fertilization rate) when the
midfollicular LH levels fell below 0.5–0.7 IU/L and ovarian
stimulation was carried out with the use of r-hFSH
monotherapy (87, 88). On the other hand, others did not
observe effect on pregnancy outcome regardless of the level
of LH suppression and type of FSH preparation (85, 86).
The effect of r-hLH in women with suppressed levels of
endogenous LH after pituitary down-regulation with GnRH
agonist was investigated in several trials (56, 58, 59, 64).
Overall, the results are equivocal, probably owing to the
heterogeneity of the study designs and the limited numbers
of patients evaluated. Only one study included in the
present systematic review suggested that women with LH
levels <0.5 IU/L could benefit from r-hLH supplementation
(64). Those authors observed higher clinical pregnancy rates
in women with deeply suppressed LH levels treated with the
use of r-hLH than in nontreated counterparts (22% vs. 5%;
P< .05), but it is noteworthy that the number of embryos
transferred was higher in the group treated with r-hLH (2.72
 0.22 vs. 1.97  0.91; P< .001). In conclusion, the
evidence available indicates that the use of GnRH agonist
could induce profound midfollicular LH suppression and
VOL. 109 NO. 4 / APRIL 2018

that the latter might affect the ovarian response to r-hFSH
stimulation. However, should this be the case, the benefit of
r-hLH supplementation remains to be determined.
Many strategies have been proposed to prevent or limit
the occurrence of OHSS (89). The clinical impact of adding
r-hLH to good-prognosis normogonadotropic women under-
going ART was investigated in a large RCT (44). The results
showed that cancellation rates owing to the risk of OHSS as
well as the development of clinical OHSS decreased in pa-
tients down-regulated with the use of GnRH agonist who
had been treated with r-hFSH and r-hLH added during the
late follicular phase. However, the mechanistic effect of r-
hLH action in such cases has yet to be determined. Conceiv-
ably, the addition of r-hLH to r-hFSH could induce a ‘‘ceiling
effect’’ in selected patients, which could favor the selection of
the ‘‘best’’ follicles. Indeed, despite the lower number of oo-
cytes recruited, the clinical pregnancy rate was higher in the
r-hLH–supplemented group compared with the r-hFSH–alone
group (44).
Poor responders to OS are one of the most challenging pa-
tient categories to treat in reproductive medicine. The diffi-
culties in the management of these women and the overall
disappointing results obtained in clinical practice are prob-
ably due to our limited understanding of the physiopathology,
poor quality of evidence, and the high heterogeneity in the
definition of poor response among trials (90). The latter two
factors are the most challenging. Indeed, in >90% of clinical
trials involving poor responders published up to 2010, no sta-
tistical differences were found in outcomes and one-half were
not adequately powered (91). Moreover, heterogeneous POR
definitions and study designs hamper interpretation of the re-
sults and consensus in this field. A recent large meta-analysis
of data available up to 2011 (84) reported significantly more
oocytes retrieved and a higher pregnancy rate with the use of
r-hFSH plus r-hLH versus r-hFSH alone in poor responders.
However, no strict criteria were adopted to identify POR,
and no distinction was made between poor responders and
hyporesponders. Therefore, it may be argued that the positive
results observed with the use of r-hLH supplementation in
poor responders could be related to the inclusion of a subpop-
ulation (hyporesponders) that seem to benefit from r-hLH
supplementation. In an attempt to identify homogeneous
groups of patients, the ESHRE Bologna criteria proposed
that patients be grouped based on ‘‘oocyte quantity’’ for
testing in prospective randomized trials (26). Only one
adequately powered multicenter RCT has been conducted so
far to assess the effect of LH supplementation in women
with a POR defined according to the ESHRE Bologna criteria
(54). No benefit was found in women cotreated with the use
of r-hLH versus patients treated with the use of r-FSH alone.
On the other hand, a post hoc analysis revealed a positive ef-
fect of LH activity in specific subgroups of POR women. These
results suggest that the POR spectrum defined according to
the ESHRE Bologna criteria is heterogeneous and may include
women with different POR profiles (70, 92). Another criticism
of the ESHRE Bologna criteria is that they do not address the
issue of oocyte quality (70, 92, 93), and their use for research
purposes has been found to be methodologically challenging
(94). The need to update these criteria has been acknowledged
VOL. 109 NO. 4 / APRIL 2018
Fertility and Sterility®
(95). It was recently suggested that poor responders to
conventional OS be stratified not only according to the
number of oocytes retrieved, but also according to ovarian
sensitivity to exogenous gonadotropins and the age-related
embryo/blastocyst aneuploidy rate (70, 92). This
classification introduced two new categories of impaired
ovarian response, namely, hyporesponders and suboptimal
responders, and could be useful in RCTs investigating the
effect of r-hLH in different categories of low-prognosis
patients.
Although hMG contains LH activity, it is derived from
hCG rather than from LH. Consequently, we did not evaluate
hMG in our analysis. Pregnancy and implantation rates were
found to be significantly higher in hyporesponders supple-
mented with the use of r-hLH than with hMG in only one pa-
per (49). The beneficial effect of r-hLH versus hMG on
pregnancy rate was confirmed in a recent large meta-
analysis (96).
CONCLUSION
Despite differences in study design, r-hLH dosage, and r-hLH
starting day, current evidence suggests that the following
groups of ART women may benefit from r-hLH supplementa-
tion during OS: 1) patients with sufficient prestimulation
ovarian reserve parameters that have an unexpected hypores-
ponse to FSH monotherapy—in these cases r-hLH can be
started either during the midfollicular phase to rescue the
ongoing cycle or on stimulation day 1 in a subsequent cycle;
and 2) women 36–39 years of age—the positive effect in terms
of implantation rate and oocyte/embryo quality observed in
donor cycles was supported by a single small RCT, so further
research is required before any definitive conclusion can be
drawn. The effect of r-hLH supplementation in preventing
OHSS remains to be established.
Although the effect of LH supplementation on ART has
been studied in a number of trials, in which conclusions
have been drawn mainly from subgroup analyses, we suggest
that trials also be conducted to investigate the effect of sup-
plementation in women who showed hyporesponse profiles
when cotreated with the use of GnRH antagonists and in
women at risk of OHSS. Finally, it remains to be established
in which of the low-prognosis categories defined by the
Poseidon group (70) that r-hLH supplementation could be
beneficial.
Acknowledgments: The authors thank Jean Ann Gilder (Sci-
entific Communication, Naples, Italy) for writing assistance.
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