357

Effects of acute prolactin manipulation on sexual drive and function

in males
T H C Krüger, P Haake, J Haverkamp, M Krämer, M S Exton,
B Saller1, N Leygraf2, U Hartmann3 and M Schedlowski
Department of Medical Psychology, University of Essen, Hufelandstrasse 55, 45122 Essen, Germany
1
Division of Endocrinology, Department of Medicine, University of Essen, 45122 Essen, Germany
2
Department of Forensic Psychiatry, University of Essen, 45122 Essen, Germany
3
Department of Clinical Psychiatry, Hanover Medical School, 30625 Hanover, Germany
(Requests for offprints should be addressed to T H C Krüger; Email: tillmann.krueger@web.de)

Abstract
The neuroendocrine response to sexual activity in humans Administration of cabergoline decreased prolactin levels
is characterized by a pronounced orgasm-dependent and significantly enhanced all parameters of sexual drive
increase of plasma levels of prolactin. In contrast to (P,0·05), function (P,0·01) and positive perception of
the well-known inhibitory effects of chronic hyperpro- the refractory period (P,0·01). Administration of pro-
lactinemia on sexual drive and function, the impact of tirelin increased prolactin concentrations and produced
acute prolactin alterations on human sexual physiology is small, but not significant reductions of sexual parameters.
unknown. Therefore, this study was designed to investi- The sexual effects observed from cabergoline were
gate the effects of acute manipulation of plasma prolactin completely abrogated by coadministration of protirelin.
on sexual behavior. Although different pharmacological sites of action of
Ten healthy males participated in a single-blind, prolactin-altering drugs have to be considered, these data
placebo-controlled, balanced cross-over design. Prolactin demonstrate that acute changes in prolactin plasma levels
levels were pharmacologically increased to high levels may be one factor modulating sexual drive and function.
(protirelin, 50 µg i.v.) or reduced to low physiological Therefore, besides a neuroendocrine reproductive reflex, a
concentrations (cabergoline, 0·5 mg p.o.). Sexual arousal post-orgasmic prolactin increase may represent one factor
and orgasm were then induced by an erotic film and modulating central nervous system centers controlling
masturbation. In addition to continuous neuroendocrine sexual drive and behavior. These findings may offer a new
and cardiovascular recordings, the quality and intensity of pharmacological approach for the treatment of sexual
the acute sexual drive, arousal, orgasm and refractory disorders.
period were assessed by extensive psychometric measures. Journal of Endocrinology (2003) 179, 357–365

Introduction of sexual stimulation, including films, masturbation and

coitus in both men and women. This series of studies have
The characterization and relevance of the neuroendocrine consistently demonstrated that plasma prolactin concen-
response to human sexual activity has received little trations are substantially increased following orgasm in
scientific attention. Previously, large methodological dif- both men and women, but unchanged following sexual
ferences in inducing sexual activity (viewing of stimulating arousal without orgasm (Krüger et al. 1998, 2003,
films, imagery of fantasies, masturbation, coitus), collecting M S Exton et al. 1999, 2001a, N G Exton et al. 2000).
blood samples (blood sampling at single discrete time Furthermore, elevations of prolactin following orgasm
points) and the experimental setting (examination cabin, remain increased over the experimental session, and
investigator entering the room) have resulted in hetero- remain raised 60 min following sexual arousal.
geneous data regarding the acute neuroendocrine response There is clinical and experimental evidence suggest-
pattern to sexual arousal, thereby ensuring that this ing that the prolactin response to orgasm may not only
phenomenon is poorly understood (Meston & Frolich affect reproductive organs (Outhit et al. 1993, Bole-Feysot
2000, Krüger et al. 2002). et al. 1998, Goffin et al. 1999), but also play a role in
Therefore, we developed a model to record continu- the control of acute sexual arousal following orgasm.
ously the neuroendocrine response to various forms Supporting this position, chronic elevations of prolactin

Journal of Endocrinology (2003) 179, 357–365 Online version via http://www.endocrinology.org

0022–0795/03/0179–357  2003 Society for Endocrinology Printed in Great Britain

Downloaded from Bioscientifica.com at 12/30/2018 10:07:23AM

via free access
358 T H C KRU
} GER and others · Prolactin and sexual behavior

(hyperprolactinemia), induced by prolactin-secreting questionnaire to exclude individuals taking medication,

tumors or as a side effect of typical neuroleptics, produce abusing drugs/alcohol, exhibiting endocrinological or
pronounced reductions of sexual drive and gonadal func- psychological disorders or fulfilling any contraindication
tions in animals (Doherty et al. 1986) and humans (Yazigi for the administration of protirelin or cabergoline.
et al. 1997, Hummer et al. 1999, Knegtering et al. 2003). Additionally, a questionnaire for the evaluation of sexual
Importantly, these effects are reversed upon pharmaco- problems/dysfunctions in males was employed. Further-
logical or surgical restoration of normal prolactin levels more, subjects were screened for psychogenic erectile
(Verhelst et al. 1999). We therefore proposed a theoretical dysfunction by questionnaire of the dual control model of
model suggesting that orgasm-induced prolactin release male sexual response (Bancroft & Janssen 2000). Subjects
may modify dopaminergic systems within the central did not show any significant differences in the specific
nervous system (CNS) that are responsible for controlling subscales (sexual inhibitory and excitatory scale) in
sexual drive and refractoriness (Krüger et al. 2002). Besides comparison with a normative sample of healthy males.
a short-loop feedback to tuberoinfundibular dopaminergic Subjects underwent a semi-structured interview and a
neurons regulating pituitary prolactin release (DeMaria physical examination by a research physician. All partici-
et al. 1999), peripheral prolactin may be able to affect pants were sexually active and reported an exclusively
dopaminergic neurons in the nigrostriatal and mesolimbo- heterosexual orientation and a relaxed attitude towards
cortical system and the medial preoptic area. Animal masturbation and erotic films. Subjects reported an average
studies have demonstrated that these sites are responsible refractory period of 18·432·30 min.
for the regulation of genital responses, appetitive behavior
and motor activity (Hull et al. 1999, Krüger et al. 2002).
Although prolactin is not able to pass the blood–brain Design and procedure
barrier due to its size (199 amino acid peptide), it may The investigation was performed using a single-blind,
reach these areas via the blood–CSF barrier and the placebo-controlled, balanced cross-over design. A
circumventricular organs (Gangong 2000, Sobrinho repeated measures design was used so that each subject
1993). participated in four experimental sessions in a different
To elucidate the function of orgasm-induced prolactin order, experiencing the conditions of: lowered prolactin,
secretion in humans, we here analyzed the effects of acute elevated prolactin, blunted prolactin (coadministration of
pharmacological manipulations of prolactin plasma levels both drugs), and unaltered prolactin (placebo); further,
on sexual arousal, orgasm and the refractory period in subjects participated in a control session where a docu-
healthy young males, utilizing a single-blind, placebo- mentary film was shown. In total, each subject participated
controlled cross-over study design. Using the established in five examinations. All sessions took place at 1600 h
experimental paradigm (Krüger et al. 2002), prolactin (Fig. 1). A one week interval separated each session, with
levels were altered to either high or low physiological the exception of the low-prolactin session, which was
concentrations. Additionally, immediately after the 60 min followed by an interval of one month due to long-lasting
session a second orgasm was induced by a pornographic effects of the prolactin-lowering drug cabergoline in few
film. This allowed examination of the subjects’ refractory persons (Andreotti et al. 1995).
period and the ability to reinitiate sexual activity. In Experiments were conducted in a separate sound-
addition to measurement of cardiovascular and neuro- attenuated room equipped with a reclining armchair, a
endocrine parameters, variables of sexual drive and func- color television and a video cassette player. All leads,
tion were evaluated using a questionnaire that has been including the blood line, passed through the wall into the
specifically developed for the assessment of acute sexual adjacent room where the cardiovascular data and blood
experiences in a laboratory setting. samples were collected, allowing subjects to be completely
isolated throughout the entire experiment. At the begin-
ning of the experiments subjects positioned themselves in
Materials and Methods the armchair in front of the screen. The cardiovascular
monitor was then engaged 20 min prior to the film and a
Subjects
steady baseline reading was obtained before the cannula
Ten healthy males (mean age 25·92·5 years, age range was inserted (15 min before the film). Depending on the
22–31 years) participated in this study after providing condition, prolactin-altering drugs or NaCl were then
written informed consent. Participants were recruited by injected i.v. Continuous blood sampling was initiated
advertisement at the University of Essen. The investi- immediately before the beginning of the film, with the
gation was conducted in accordance with the guide- samples divided into nine 10 min intervals (Krüger et al.
lines proposed in The Declaration of Helsinki and was 1998, M S Exton et al. 1999, 2001a,b, N G Exton 2000).
approved by the Ethics Committee for investigations Specifically, sample 0 represented a basal value before i.v.
involving human subjects at the University Clinics of drug administration. Samples 1 and 2 represented basal
Essen. Participants completed a general medical/health value during the neutral stimulus, sample 3 represented
Journal of Endocrinology (2003) 179, 357–365 www.endocrinology.org
Downloaded from Bioscientifica.com at 12/30/2018 10:07:23AM
via free access
 Prolactin and sexual behavior · T H C KRU
} GER and others 359

'RFXPHQWDU\

&RQWUROVHVVLRQ

'RFXPHQWDU\ (URWLF 'RFXPHQWDU\ (URWLF

$QWLFLSDWLRQ 0DVWXUEDWLRQ
0DVWXUEDWLRQ

&DEHUJROLQH 1D&O /RZSURODFWLQVHVVLRQ

3ODFHER 75+ +LJKSURODFWLQVHVVLRQ

&DEHUJROLQH 75+ %OXQWHGSURODFWLQVHVVLRQ

3ODFHER 1D&/ 3ODFHERVHVVLRQ

K  PLQ PLQ PLQ PLQ PLQ  PLQ

2UDO       
DSSOLFDWLRQ
  6DPSOH
,QWHUYDO
&DQQXOD ,QWUDYHQRXV
LQVHUWHG LQMHFWLRQ
&RQWLQXRXVEORRGVDPSOLQJ
&RQWLQXRXVDVVHVVPHQWRIFDUGLRYDVFXODU SDUDPHWHUV
3V\FKRPHWU\EHJLQQLQJ DQG HQGRIHDFK VHVVLRQ
Figure 1 Experimental paradigm for investigating the effects of acute prolactin manipulation on sexual arousal and orgasm in a laboratory
setting. Plasma sample 0 represented a basal value before i.v. drug administration. Samples 1 and 2 represented basal values during the
neutral stimulus, sample 3 represented the response to film-induced sexual arousal, sample 4 demonstrated the response to orgasm, the
next two samples (5 and 6) displayed the recovery phase, sample 7 again demonstrated sexual arousal and orgasm/reinitiation of sexual
activity, with sample 8 representing another post-orgasmic phase.

the response to film-induced sexual arousal, sample 4 sequences consisted of heterosexual couples stimulating
demonstrated the response to orgasm, the next two each other and having intercourse. All visual stimulation
samples (5 and 6) displayed the recovery phase, sample 7 had been established in previous studies (Krüger et al.
again demonstrated sexual arousal and orgasm/reinitiation 1998, M S Exton et al. 1999, 2001a,b, N G Exton 2000).
of sexual activity, with sample 8 representing another
post-orgasmic phase.
In the experimental sessions a documentary film was
observed for 20 min, followed by 20 min of a pornographic Pharmacological prolactin manipulation
film, and a further 20 min documentary. Following Due to ethical and practical difficulties, the use of syn-
10 min of the pornographic film, subjects were asked thetic or purified prolactin or prolactin antagonists to alter
to masturbate until orgasm. Finally, another 10 min of plasma prolactin has not been established in humans.
pornographic film were presented for the examination of Nevertheless, manipulation of prolactin release may be
refractory period and reinitiation of sexual arousal and conducted at the hypothalamus–pituitary level, where
orgasm. Immediately after the session, subjects completed the regulation of prolactin mainly remains under tonic
the psychometric scales. inhibitory dopaminergic control (Macleod & Lehmeyer
Subjects also participated in a control session, where a 1974).
documentary film was shown for 70 min. Together, every Prolactin levels were lowered by oral administration of
subject participated in five different sessions in a counter- 0·5 mg of the D2-receptor agonist cabergoline (Dostinex,
balanced order. Different documentary and pornographic Pharmacia & Upjohn), which is well-tolerated without
sequences were employed throughout the sessions so as to significant side effects in this dosage (Andreotti et al.
avoid habituation effects. The documentary consisted of 1995). Effects on other, nonprolactinergic endocrine vari-
travel stories and natural science, whereas the erotic ables have not been reported. Cabergoline was given the
www.endocrinology.org Journal of Endocrinology (2003) 179, 357–365
Downloaded from Bioscientifica.com at 12/30/2018 10:07:23AM
via free access
360 T H C KRU
} GER and others · Prolactin and sexual behavior

evening before the examination, thus ensuring decreased was delayed by 2 min. Blood was stored on ice until the
prolactin levels throughout the session (Fig. 1). samples were centrifuged at 4 C and stored at – 70 C
Prolactin was increased by i.v. injection of 50 µg until assayed (Krüger et al. 1998, M S Exton et al. 1999,
protirelin (Relefact TRH 200/400, Hoechst Marion 2001a,b, N G Exton 2000).
Roussell), which is one-eighth to a quarter dose of that All samples of each participant for a particular hor-
used diagnostically in the thyrotropin-releasing hormone mone were assayed in duplicate within the same assay.
(TRH) test and well-tolerated in this dosage. Protirelin Catecholamine plasma levels were measured by HPLC
was given at the beginning of the experiment, thus (Ehrenreich et al. 1997, Smedes et al. 1982). The intra-
producing the desired prolactin increase during the and interassay variability for noradrenaline were 6·2 and
period of sexual arousal and orgasm (Garbutt et al. 1994, 8·0% respectively, and 4·0 and 5·1% respectively for
Horita 1998). Consecutive increases of thyroxine and adrenaline. All other hormones like thyrotropin (TSH),
triiodothyronine occur with a certain latency. prolactin, follicle-stimulating hormone (FSH), luteinizing
In another condition participants received a combi- hormone (LH), testosterone and cortisol were detected
nation of 50 µg protirelin and 0·5 mg cabergoline. The by the Automated Chemiluminescence-Immunoassay-
administration of both drugs was done to allow detection System 180 (ACS: Centaur; Chiron Diagnostics,
of the prolactin-independent effects of cabergoline and Leverkusen, Germany). The intra- and interassay coeffi-
protirelin. cients of variance were 3·3 and 3·5% for TSH, 2·5 and
The time kinetics of the effects of protirelin and 3·6% for prolactin, 2·8 and 4·6% for FSH, 4·7 and 6·3% for
cabergoline on plasma prolactin were examined in a LH, 5·6 and 6·6% for testosterone and 4·5 and 6·4% for
preliminary study and controlled throughout the experi- cortisol respectively.
mental sessions. The dosages of both substances were
adjusted with the aim of achieving prolactin levels that Psychometric measures To the best of our knowledge
represented either low physiological concentrations or there is no standardized questionnaire for the evaluation of
levels mirroring approximately those produced by orgasm acute sexual experience in an experimental situation.
(Krüger et al. 1998, M S Exton et al. 1999, 2001a). The Therefore, we designed an acute sexual experience
whole examination was placebo-controlled. scale (ASES), containing six subscales with 52 items.
Side effects of drug administration on nonsexual The questionnaire evaluates different characteristics of
parameters were screened by a specific questionnaire. appetitive, consummatory and refractory sexual behavior
There were no significant differences between the verum in males. One part of the questionnaire consists of control
and placebo conditions. items, for evaluating parameters such as the occurrence of
orgasm and ejaculation latency. However, the investigators
also registered this by online observation of cardiovascular
Measures measurements (rapid decrease of heart rate and blood
pressure immediately after orgasm), and by subject regis-
Cardiovascular measures The cardiovascular param- tration of the start and end of masturbation via intercom.
eters heart rate and systolic and diastolic blood pressure Another part of the questionnaire consists of self-reporting
were monitored continuously via a finger cuff connected ratings of sexual functioning using visual analog rating
to a blood pressure monitor (Finapres; Ohmeda, scales (0–100, from ‘not at all’ to ‘extremely’). The scales
Louisville, CO, USA) in the adjoining room. Cardiovas- examined sexual functioning both in absolute values and as
cular activity was recorded every 30 s, and the heart rate compared with normally experienced sexuality in a real
and blood pressure values were averaged over 10 min life situation such as masturbation and sexual intercourse.
intervals and analyzed in parallel with the 10 min interval In detail, the first subscale, ‘appetitive phase’, assessed
blood samples (Krüger et al. 1998). features of sexual arousability, lust and desire during the
first part of the pornographic video presentation where
Endocrine measures For continuous blood sampling an subjects remained passive (e.g. ‘Please estimate the inten-
i.v. cannula (Kliniject, 18 G, Klinika Medical GmbH, sity of sexual arousal while watching the pornographic
Usingen, Germany) was inserted into a forearm vein of the video’). The second subscale ‘consummatory phase’ evalu-
nondominant arm and connected to a 1·25 m heparinized ated the quality, intensity and duration of orgasm and
silicon tube (inner diameter 2·0 mm; Reichelt Chemie, sexual release associated with orgasm during the second
Heidelberg, Germany). The silicon tubing passed through part of the pornographic sequence where subjects were
the wall into the adjoining room and was driven by a asked to masturbate (e.g. ‘Please estimate the intensity of
peristaltic pump (Fresenius, Homburg, Germany). Blood your orgasm’). The third subscale ‘refractory phase’ evalu-
flow was adjusted to 2 ml/min, collected into EDTA ated both negative aspects of refractoriness like tiredness,
tubes (Sarstedt, Nümbrecht, Germany) and divided into recovery and soberness (negative scale, e.g. ‘Please esti-
10 min intervals. The dead space of the blood collection mate the grade of tiredness you perceived after orgasm’)
system was about 4 ml and the collection of each sample and positive aspects like sexual release and relaxation
Journal of Endocrinology (2003) 179, 357–365 www.endocrinology.org
Downloaded from Bioscientifica.com at 12/30/2018 10:07:23AM
via free access
 Prolactin and sexual behavior · T H C KRU
} GER and others 361

(positive scale, e.g. ‘Please estimate the feeling of being

far away after orgasm’). The fifth and sixth scale again
assessed the appetitive and consummatory phase during
the reinitiation of sexual arousal and orgasm.

Statistical analyses
Cardiovascular and endocrine data from all subjects
were analyzed by a two-factor repeated measures
(conditiontime) ANOVA. If not otherwise stated we
report the conditiontime interaction effect. Planned,
paired-samples t-tests were conducted on each scale
of the questionnaire for ASES between the cabergoline,
protirelin, cabergoline plus protirelin and placebo con-
ditions. An
of 0·05 was considered statistically significant
for all analyses.

Results

Cardiovascular measures
In parallel to increased subjective sexual arousal during the
pornographic sequences, participants revealed a transient Figure 2 (a) Time course of effects of sexual arousal and orgasm
increase in heart rate (F[6,54]=6·07, P,0·001), systolic on plasma prolactin levels during the first and second sequence of
sexual activity in the group receiving placebo compared with a
(F[6,54]=9·38, P,0·001) and diastolic (F[6,54]=8·87, control condition (documentary). (b) Prolactin plasma levels in the
P,0·001) blood pressure during sexual arousal and orgasm groups with high prolactin (protirelin administration), low prolactin
(interval three, four and seven), with an immediate decline (cabergoline) or reversed prolactin (cabergoline+protirelin). Values
after orgasm to baseline levels. No significant differences are expressed as means S.E.
between the experimental conditions were found (data not
shown).
during the two sequences of sexual activity (mean 16·3
and 8·0 ng/ml respectively) and a further decline to
Endocrine measures
physiological levels at the end of the examination (5·5 ng/
In the placebo condition, prolactin plasma levels increased ml) (F[8,72]=37·18, P,0·001) (Fig. 2b).
an average of 50% during orgasm and remained elevated TSH plasma levels were significantly increased when
thereafter (F[8,72]=6·56, P,0·001). A further prolactin protirelin, or the combination of protirelin and cabergoline
increase was observed during the second orgasm in the was administered (F[8,72]=54·38, P,0·001; F[8,72]=
seventh interval. Prolactin plasma concentrations and all 38·303, P,0·001 respectively), but were unaffected after
other endocrine variables remained unchanged during the placebo or cabergoline administration. Thyroxine and
documentary film (Fig. 2a). triiodothyronine remained unaltered in all conditions
The group receiving cabergoline showed decreased (Table 1).
prolactin concentrations throughout the session, with Plasma concentrations of adrenaline increased signifi-
plasma levels of approximately 2·5 ng/ml (F[8,72]=6·01, cantly, whereas noradrenaline only tended to increase
P,0·001) (Fig. 2b). during the two sequences of sexual activity in the placebo
The administration of 50 µg protirelin induced an condition (F[8,72]=3·84, P,0·01; F[8,72]=1·82, P=
immediate increase of prolactin plasma levels, achieving 0·09 respectively), showing no significant differences be-
initial concentrations of 28 ng/ml on average, declining tween the different conditions (Tables 2 and 3). Plasma
consistently towards slight supraphysiological levels during concentrations of FSH, LH, testosterone and cortisol were
sexual arousal and orgasm (20·5 ng/ml), and decreased unaltered by sexual activity, with this effect independent
further towards upper physiological levels during the of the experimental condition (data not shown).
second period of sexual activity (F[8,72]=18·8, P,0·001)
(Fig. 2b).
The group receiving cabergoline and protirelin initially Subjective sexual functioning
demonstrated prolactin levels of more than 20 ng/ml, with In the low-prolactin (cabergoline administration) and
a consistent decrease towards upper physiological levels placebo conditions, all subjects reported having an
www.endocrinology.org Journal of Endocrinology (2003) 179, 357–365
Downloaded from Bioscientifica.com at 12/30/2018 10:07:23AM
via free access
362 T H C KRU
} GER and others · Prolactin and sexual behavior

Table 1 Plasma levels of TSH (U/ml, means with S.E.) in the different experimental conditions and in the control condition (documentary).
Samples 0–8 represent the different phases of sexual activity as explained in Fig. 1

Sample no.
0 1 2 3 4 5 6 7 8

Low prolactin 0·83 (0·08) 0·76 (0·07) 0·74 (0·08) 0·76 (0·08) 0·77 (0·08) 0·83 (0·10) 0·86 (0·06) 0·83 (0·10) 0·91 (0·14)
High prolactin 1·18 (0·08) 4·46 (0·48) 5·46 (0·54) 5·13 (0·53) 4·63 (0·43) 4·08 (0·34) 3·72 (0·31) 2·95 (0·25) 2·78 (0·22)
Reversed prolactin 1·01 (0·14) 3·95 (0·53) 5·13 (0·70) 4·89 (0·70) 4·55 (0·68) 3·94 (0·58) 3·56 (0·55) 2·94 (0·44) 2·69 (0·38)
Placebo 1·23 (0·17) 1·12 (0·15) 1·08 (0·13) 1·09 (0·14) 1·09 (0·14) 1·07 (0·14) 1·08 (0·14) 1·21 (0·17) 1·36 (0·17)
Control (documentary) 0·84 (0·09) 0·76 (0·07) 0·74 (0·08) 0·76 (0·08) 0·77 (0·09) 0·83 (0·10) 0·86 (0·06) 0·83 (0·10) 0·92 (0·14)

Table 2 Plasma levels of adrenaline (pg/ml, means with S.E.) in the different experimental conditions and in the control condition
(documentary). Samples 0–8 represent the different phases of sexual activity as explained in Fig. 1

Sample no.
0 1 2 3 4 5 6 7 8

Low prolactin 43·8 (9·0) 33·1 (9·5) 32·3 (8·9) 48·5 (10·0) 37·2 (8·4) 26·5 (6·3) 27·5 (6·7) 40·7 (8·8) 37·9 (9·4)
High prolactin 36·7 (6·5) 33·1 (7·4) 33·3 (6·4) 45·0 (9·3) 41·9 (6·3) 28·5 (3·8) 26·5 (4·1) 32·6 (5·5) 37·6 (6·2)
Reversed prolactin 50·7 (10·6) 59·5 (10·8) 51·1 (7·4) 69·5 (12·3) 87·7 (24·9) 48·4 (10·1) 46·3 (10·4) 51·6 (8·0) 51·3 (7·8)
Placebo 41·6 (7·5) 34·5 (5·8) 40·0 (8·2) 50·0 (11·1) 42·1 (6·0) 31·0 (4·5) 29·2 (4·6) 37·3 (7·3) 38·6 (6·7)
Control (documentary) 39·5 (7·7) 29·2 (6·0) 30·2 (4·8) 27·9 (4·4) 25·8 (4·7) 26·5 (5·0) 27·7 (5·8) 37·4 (6·7) 37·5 (5·6)

orgasm during both the first and second sequence of and second sequence of sexual activity (t[9]=2·465,
sexual activity. Two participants in the reversed P,0·05; t[9]=3·498, P,0·01 respectively). Additionally,
prolactin (cabergoline and protirelin), and one subject in positive aspects of the refractory period such as
the elevated prolactin (protirelin) condition reported sexual release and relaxation were significantly enhanced
having difficulties in achieving an orgasm during the (positive scale) (t[9]=3·534, P,0·01), whereas the nega-
first or second sequence of sexual activity. Figure 3 tive scale of refractory period did not reveal any differences
displays the ejaculation latency indicated by the (t[9]=0·475, P=0·65) (Fig. 3).
subjects. There was a significant difference between However, reversed prolactin plasma concentration after
the high and reversed prolactin condition compared administration of cabergoline in combination with protire-
with placebo during the first sequence (t[9]=2·822, lin inverted this effect, with participants showing no
P,0·05; t[9]=
2·799, P,0·05 respectively) and alteration of sexual drive and function during the first
between the low-prolactin and high-prolactin conditions (t[9]=1·017, P=0·34; t[9]=1·058, P=0·32 respectively)
during the reinitiation of sexual activity (t[9]=
2·875, and second sequences of sexual activity (t[9]=1·565,
P,0·05). P=0·16; t[9]=0·007, P=0·995 respectively), as well as the
Furthermore, cabergoline-induced hypoprolactinemia refractory period (negative scale: t[9]=1·373, P=0·20;
significantly enhanced all parameters of sexual drive and positive scale: t[9]=1·645, P=0·14) (Fig. 3).
function, as measured by the ASES, including appetitive Increasing prolactin concentrations by administration of
and consummatory sexual behavior during the first protirelin only tended to reduce sexual drive and function
(t[9]=2·681, P,0·05; t[9]=3·383, P,0·01 respectively) during the first (t[9]=1·102, P=0·30; t[9]=1·500, P=0·17

Table 3 Plasma levels of noradrenaline (pg/ml, means with S.E.) in the different experimental conditions and in the control condition
(documentary). Samples 0–8 represent the different phases of sexual activity as explained in Fig. 1

Sample no.
0 1 2 3 4 5 6 7 8

Low prolactin 273 (28) 157 (27) 334 (173) 211 (32) 218 (32) 169 (29) 168 (25) 318 (35) 329 (42)
High prolactin 261 (29) 243 (38) 216 (33) 237 (31) 301 (49) 244 (43) 235 (33) 371 (48) 410 (157)
Reversed prolactin 337 (44) 328 (56) 298 (50) 369 (67) 476 (118) 455 (108) 310 (60) 476 (76) 512 (80)
Placebo 280 (50) 235 (34) 212 (32) 242 (30) 290 (38) 229 (30) 210 (30) 342 (53) 372 (43)
Control (documentary) 305 (45) 202 (28) 209 (26) 198 (30) 189 (30) 190 (29) 213 (29) 334 (44) 392 (66)

Journal of Endocrinology (2003) 179, 357–365 www.endocrinology.org

Downloaded from Bioscientifica.com at 12/30/2018 10:07:23AM
via free access
 Prolactin and sexual behavior · T H C KRU
} GER and others 363

Figure 3 Effects of low prolactin (cabergoline administration), high prolactin

(protirelin), reversed prolactin (cabergoline+protirelin) and placebo on
ejaculation latency, sexual drive, consummatory sexual experience and
refractory period during the first and second (reinitiation) sequence of sexual
activity, as measured by the ASES using control items (ejaculation latency) and
visual analog rating scales (all other parameters). Except for ejaculation latency
(min), questionnaire values represent percent of maximum sexual experience.
Values are expressed as means S.E. **P<0·01; *P<0·05.

respectively) and second sequences of sexual activity Discussion

(t[9]=1·566, P=0·15; t[9]=0·899, P=0·40 respectively) In a series of studies we have consistently demonstrated
(Fig. 3). that prolactin plasma concentrations are substantially
www.endocrinology.org Journal of Endocrinology (2003) 179, 357–365
Downloaded from Bioscientifica.com at 12/30/2018 10:07:23AM
via free access
364 T H C KRU
} GER and others · Prolactin and sexual behavior

increased for over 1 h following orgasm in men and releasing or -inhibiting drugs. To date, prolactin or
women, but unchanged following sexual arousal without prolactin receptor antagonists are unavailable, unaffordable
orgasm (Krüger et al. 1998, 2003; M S Exton et al. 1999, or not safe for use in humans. Consequently, we used the
2001a, N G Exton et al. 2000). Therefore, the present dopamine agonist cabergoline, which reliably decreases
investigation aimed to examine the physiological impact of prolactin plasma levels. Dopamine agonists have been
acute alterations of prolactin on sexual parameters by shown to facilitate not only animal (Hull et al. 1999) but
pharmacological manipulation of prolactin levels in healthy also human sexual behavior (Giuliano & Allard 2001).
men. However, it seems that the enhancing effects of decreased
This study demonstrates that acute changes in prolactin prolactin levels on sexual drive and function are not
levels may be one causal factor that modulates acute sexual exclusively explainable by the direct dopaminergic effects
drive and function after orgasm. Specifically, increasing of cabergoline. Indeed, increasing prolactin by co-
prolactin concentrations by protirelin administration pro- administration of protirelin completely abrogated the
duced significantly longer ejaculation latency during the sexual increases observed under single cabergoline admin-
first sequence of sexual activity, but only small reductions istration. Thus, dopaminergic properties of cabergoline
of sexual drive and function. In contrast, cabergoline- may regulate the increase in sexual experience, but this is
induced hypoprolactinemia significantly enhanced all dependent on prolactin levels.
parameters of sexual drive and function, as measured by It is important to note the novel methods of recording
the ASES. Further, reversal of prolactin plasma levels by physiological and psychological data of the sexual experi-
coadministration of cabergoline and protirelin resulted in ence. Objective assessment of sexual parameters like penile
participants showing no alterations of sexual drive and tumescence or rigidity are not practical in this kind of
function in comparison with the placebo condition. These investigation. Therefore, orgasm was detected online by an
data suggest a tight association between small, acute increase of cardiovascular activity, followed by a rapid
changes in plasma prolactin and sexual drive and function. decrease immediately after orgasm; analysis of prolactin
Indeed, we have recently proposed that orgasm- concentrations and direct report from the subjects via
induced prolactin release may be a neuroendocrine reflex intercom were also used. The combination of these
for maintaining reproductive functions necessary for methodologies allowed accurate registration of ejaculation
fertility, conception and pregnancy. Furthermore, we latency. Moreover, certain aspects of sexual behavior like
theorized that prolactin may represent a negative feed- quality and intensity of orgasm, or characteristics of the
back mechanism whereby this hormone may modify the refractory period are hardly detectable with objective
activity of dopaminergic neurons in the CNS that are techniques. To date there is no standardized questionnaire
regarded as controlling sexual motivation and function for the assessment of acute sexual experience in such an
(Krüger et al. 2002). Nevertheless, this hypothesis was based experimental setting. Consequently, most psychometric
on the knowledge that chronic hyperprolactinemia produces sexual data were recorded by the ASES, which remains to
dramatic reductions in sexual motivation and function be standardized/validated. Nevertheless, the consistency
(Doherty et al. 1986, Yazigi et al. 1997, Cutler 2003). The and strength of the relationship between altered prolactin
current study supports the hypothesis, as in addition to high, levels and scores in the ASES allow a certain confidence
chronic changes in plasma prolactin observed in hyper- in the demonstrated impact of hormonal alterations on
prolactinemia (.100 ng/ml), acute changes in the normal parameters of sexual drive, consummation and refractori-
physiological levels of prolactin may also modify sexual ness. Undoubtedly, further studies are needed to further
motivation and function. However, the current data do not develop this kind of questionnaire for experimental sex
demonstrate a role for prolactin as a simple and direct research.
negative feedback mechanism. For instance, apart from In conclusion, these data corroborate the hypothesis
ejaculation latency, protirelin-induced hyperprolactinemia that, beside a neuroendocrine reproductive reflex, acute
did not lead to the significant reduction of sexual parameters prolactin alterations following orgasm may be one factor
that would be expected in a tight feedback loop. Further- modulating acute sexual drive and behavior. However, the
more, in the placebo condition, the sexual experience of the study further demonstrates that post-orgasmic increases of
second sequence, where prolactin levels were already in- prolactin probably do not represent a direct negative
creased, was not different to the first episode. Thus, these feedback mechanism to the CNS but are likely to be one
data suggest that although prolactin is important in the signal among a complex interaction of neuropeptides,
post-orgasmic regulation of sexual behavior, it is likely to be monoamines and neurotransmitters controlling sexual
one signal within a network of psycho-neuroendocrine behavior (Argiolas 1999, Pfaus 1999, Meston & Frohlich
regulation of acute sexual experience. 2000). Besides the theoretical importance of these data, the
As a further caveat, we must note that this study was effects of cabergoline-induced hypoprolactinemia may
limited by methodological challenges. The manipulation have an immense clinical impact for the application of
of prolactin plasma levels in humans was achieved by dopamine agonists in the treatment of both disorders of
indirect means, via the administration of prolactin- sexual drive.
Journal of Endocrinology (2003) 179, 357–365 www.endocrinology.org
Downloaded from Bioscientifica.com at 12/30/2018 10:07:23AM
via free access
 Prolactin and sexual behavior · T H C KRU
} GER and others 365

Funding Giuliano F & Allard J 2001 Dopamine and sexual function.

International Journal of Impotence Research 13 S18–S28.
Goffin V, Binart N, Clement-Lacroix P, Bouchard B, Bole-Feysot C,
This study was supported by a grant from the Deutsche Edery M, Lucas BK, Touraine P, Pezet A, Maaskant R et al. 1999
Forschungsgemeinschaft (Sche 341/10–1). From the molecular biology of prolactin and its receptor to the
lessons learned from knockout mice models. Genetic Analysis 15
189–201.
Horita A 1998 An update on the CNS actions of TRH and its
References analogs. Life Sciences 62 1443–1448.
Hull EM, Lorraine DS, Du J, Matuszewich L, Lumley LA, Putnam
Andreotti AC, Pianezzola E, Persiani S, Pacciarini MA, Benedetti MS SK & Moses J 1999 Hormone-neurotransmitter interactions in the
& Pontiroli AE 1995 Pharmacokinetics, pharmacodynamics, and control of sexual behavior. Behavioural Brain Research 105 105–116.
tolerability of cabergoline, a prolactin-lowering drug, after Hummer M, Kemmler G, Kurz M, Kurzthaler I, Oberbauer H &
administration of increasing oral dose (0·5, 1·0, and 1·5 milligrams) Fleischhacker WW 1999 Sexual disturbance during clozapine and
in healthy male volunteers. Journal of Clinical Endocrinology and haloperidol treatment for schizophrenia. American Journal of Psychiatry
Metabolism 80 841–845. 156 631–633.
Argiolas A 1999 Neuropeptides and sexual behavior. Neuroscience and Knegtering M, van der Moolen AE, Castelein S, Kluiter H & van den
Biobehavioral Reviews 23 1127–1142. Bosch RJ 2003 What are the effects of antipsychotics on sexual
Bancroft J & Janssen E 2000 The dual control model of male sexual dysfunctions and endocrine functioning? Psychoneuroendocrinology 28
response: a theoretical approach to psychogenic erectile dysfunction. (Suppl) 109–123.
Neuroscience and Biobehavioral Reviews 24 571–579. Krüger THC, Exton MS, Pawlak C, von zur Mühlen A, Hartmann U
Bole-Feysot C, Goffin V, Edery M, Binart N & Kelly PA 1998 & Schedlowski M 1998 Neuroendocrine and cardiovascular
Prolactin (PRL) and its receptor: actions, signal transduction response to sexual arousal and orgasm in men.
pathways and phenotypes observed in PRL receptor knockout Psychoneuroendocrinology 23 401–411.
mice. Endocrine Reviews 19 225–268. Krüger THC, Haake P, Hartmann U, Schedlowski M & Exton MS
DeMaria JE, Lerant AA & Freeman ME 1999 Prolactin activates all 2002 Orgasm-induced prolactin secretion: feedback control of
three populations of hypothalamic neuroendocrine dopaminergic sexual drive? Neuroscience and Biobehavioral Reviews 26 31–44.
neurons in ovariectomized rats. Brain Research 837 236–241. Krüger THC, Haake P, Chereath D, Knapp W, Jannsen OE, Exton
Cutler AJ 2003 Sexual dysfunction and antipsychotic treatment. MS, Schedlowski M & Hartmann U 2003 Specificity of the
Psychoneuroendocrinology 28 69–82. neuroendocrine response to orgasm during sexual arousal in men.
Doherty PC, Baum MJ & Todd RB 1986 Effects of chronic Journal of Endocrinology 177 57–64.
hyperprolactinemia on sexual arousal and erectile function in male Macleod RM & Lehmeyer JE 1974 Studies on the mechanism of the
rats. Neuroendocrinology 42 368–375. dopamine-mediated inhibition of prolactin secretion. Endocrinology
Ehrenreich H, Schuck J, Stender N, Pilz J, Gefeller O, Schilling L, 94 1077–1085.
Poser W & Kaw S 1997 Endocrine and hemodynamic effects of Meston CM & Frohlich PF 2000 The neurobiology of sexual function.
stress versus systemic CRF in alcoholics during early and medium Archives of General Psychiatry 57 1012–1030.
term abstinence. Alcoholism, Clinical and Experimental Research 21 Outhit A, Morel G & Kelly PA 1993 Visualization of gene expression
1285–1293. of short and long forms of prolactin receptor in the rat reproductive
Exton MS, Bindert A, Krüger THC, Scheller F, Hartmann U & tissues. Biology of Reproduction 49 528–536.
Schedlowski M 1999 Cardiovascular and endocrine alterations after Pfaus JG 1999 Neurobiology of sexual behavior. Current Opinion in
masturbation-induced orgasm in women. Psychosomatic Medicine 61 Neurobiology 9 751–758.
280–289. Smedes F, Kraak JC & Poppe H 1982 Simple and fast solvent
Exton MS, Krüger THC, Koch M, Paulson E, Knapp W, Hartmann extraction system for selective and quantitative isolation of
U & Schedlowski M 2001a Coitus-induced orgasm stimulates adrenaline, noradrenaline and dopamine from plasma and urine.
prolactin secretion in healthy subjects. Psychoneuroendocrinology 26 Journal of Chromatography 231 25–39.
287–294. Sobrinho LG 1993 The psychogenic effects of prolactin. Acta
Exton MS, Krüger THC, Bursch N, Haake P, Knapp W, Endocrinologica 129 S38–S40.
Schedlowski M & Hartmann U 2001b Neuroendocrine response to Verhelst J, Abs R, Maiter D, van den Bruel A, Vandeweghe M,
masturbation-induced orgasm in healthy men following a 3-week Velkeniers B, Mockel J, Lamberigts G, Petrossians P, Coremans P
sexual abstinence. World Journal of Urology 19 377–382. et al. 1999 Cabergoline in the treatment of hyperprolactinemia: a
Exton NG, Truong TC, Exton MS, Wingenfeld SA, Leygraf N, study in 455 patients. Journal of Clinical Endocrinology and Metabolism
Saller B, Hartmann U & Schedlowski M 2000 Neuroendocrine 84 2518–2522.
response to film-induced sexual arousal in men and women. Yazigi RA, Quintero CH & Salameh WA 1997 Prolactin disorders.
Psychoneuroendocrinology 25 187–199. Fertility and Sterility 67 215–225.
Gangong WF 2000 Circumventricular organs: definition and role in
the regulation of endocrine and autonomic function. Clinical and Received 2 May 2003
Experimental Pharmacology and Physiology 27 422–427.
Garbutt JC, Mayo JP, Little KY, Gillette GM, Mason GA, Dew B &
Accepted 26 August 2003
Prange AJ 1994 Dose-response studies with Protirelin. Archives of Made available online as an
General Psychiatry 51 875–883. Accepted Preprint on 28 August 2003

www.endocrinology.org Journal of Endocrinology (2003) 179, 357–365

Downloaded from Bioscientifica.com at 12/30/2018 10:07:23AM
via free access