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ORIGINAL PAPER

Prenatal Exposure to Progesterone Affects Sexual Orientation in Humans

JuneM. Reinisch1,2,3 • Erik Lykke Mortensen3,4 • Stephanie A. Sanders1,5

Received: 18 June 2013 / Revised: 15 December 2016 /Accepted: 15 December 2016 / Published online: 3 April 2017

� Springer Science+Business Media New York 2017

Abstract Prenatal sexhormone levelsaffectphysicalandbehav-

ioralsexualdifferentiationinanimalsandhumans.Althoughprena-

tal hormones are theorized to influence sexual orientation in

humans, evidence is sparse. Sexual orientationvariables for 34

prenatally progesterone-exposed subjects (17 males and 17

females) were compared to matched controls (M age= 23.2

years). A case–control double-blind design was used drawing

on existing data from the US/Denmark Prenatal Development

Project. Index cases were exposed to lutocyclin (bioidentical

progesterone=C21H30O2;MW:314.46)andnootherhormonal

preparation. Controls were matched on 14 physical, medical,

and socioeconomic variables. A structured interview conduc-

ted by a psychologist and self-administered questionnaires

were used to collect data on sexual orientation, self-identifi-

cation,attractiontothesameandothersex,andhistoryofsexual

behavior with each sex. Compared to the unexposed, fewer

exposedmalesandfemales identifiedasheterosexualandmore

of them reported histories of same-sex sexual behavior, attrac-

tiontothesameorbothsexes,andscoredhigheronattractionto

males.Measuresofheterosexualbehaviorandscoresonattrac-

tiontofemalesdidnotdiffersignificantlybyexposure.Wecon-

clude that, regardless of sex, exposure appeared to be associ-

atedwithhigherratesofbisexuality.Prenatalprogesteronemaybe

an underappreciated epigenetic factor in human sexual and psy-

chosexual development and, in light of the current prevalence of

progesterone treatment during pregnancy for a variety of preg-

nancy complications, warrants further investigation. These data

ontheeffectsofprenatalexposuretoexogenousprogesteronealso

suggest a potential role for natural early perturbations in proges-

terone levels in the development of sexual orientation.

Keywords Sexual orientation � Prenatal progesterone exposure � Bisexuality � Sexual behavior

Introduction

Although prenatal gonadal hormones have been theorized to

influence sexual orientation in humans, other than recent

research using a surrogate measure (2D:4D digit ratio) for pre-

natalandrogenexposure(Hiraichi,Sasaki,Shikishima,&Ando,

2012; Wong & Hines, 2015), evidence from studies of exoge-

noushormoneexposure is sparse (Adkins-Regan, 1988;Ellis&

Ames, 1987; Gooren, 2006; Hines, 2011; Hines, Constanti-

nescu, & Spencer, 2015; Meyer-Bahlburg, 1984). Despite rel-

atively frequent current administration of exogenous proges-

terone to pregnant womenwith a variety of clinical problems,

even less attention has been paid to the possible role of prenatal

exposure to progesterone on any aspect of human sexual and

psychosexual development (Kester, Green, Finch,&Williams,

1980; Reinisch, Ziemba-Davis, & Sanders, 1991; Sanders &

Reinisch, 1985; Wagner, 2008). Perhaps this is due to the ele-

vated levels of natural progesterone present during gestation lead-

ing to the assumption that additional exogenous doses would not

affect these aspects of development.

& June M. Reinisch [email protected]

1 The Kinsey Institute for Research in Sex, Gender and

Reproduction, Indiana University, Morrison Hall 313,

Bloomington, IN 47405, USA

2 The Museum of Sex, New York, NY, USA

3 Institute of Preventive Medicine, Copenhagen University

Hospital, Copenhagen, Denmark

4 Department of Public Health, University of Copenhagen,

Copenhagen, Denmark

5 Department of Gender Studies, Indiana University,

Bloomington, IN, USA

123

Arch Sex Behav (2017) 46:1239–1249

DOI 10.1007/s10508-016-0923-z

The prenatal hormone or neuroandrogenic theory of sexual

orientation (Ellis & Ames, 1987; Gooren, 2006; Hines, 2010;

Meyer-Bahlburg, 1984) assumes that heterosexuality is an in-

herent part of ‘‘normal’’ sexual differentiation and that homo-

sexuality (as evidenced by self-identification, same-sex sexual

behavior, or attraction/desire) is a result of perturbations in the

typical prenatal hormone environment. Specifically, the theory

suggests that homosexuality is the result of insufficient prenatal

androgenexposureoraction inmalesandexcessprenatalandro-

gen exposure in females during sensitive periods of early devel-

opment.Thus,homosexuality isviewedassomedegreeof femi-

nization and/or demasculinization of males and of masculin-

izationand/ordefeminizationof females.Bisexuality inhumans

isoften thoughtofas‘‘partialhomosexuality’’orasmovingaway

from‘‘exclusive heterosexuality’’toward amiddle point along a

bipolar unidimensional continuum between exclusive hetero-

sexuality and exclusive homosexuality (Kinsey, Pomeroy, &

Martin, 1948).ThisbipolarKinseyscalemodel implies a trade--

off betweenheterosexuality andhomosexuality—themorehomo-

sexual, the lessheterosexual (seeSanders,Reinisch,&McWhirter,

1990).

For ethical reasons, support for the formative role of prenatal

sex hormones in the development of sexual orientation is based

primarily on experiments with animals (Adkins-Regan, 1988;

Balthazart, 2011; Hines, 2011; Meyer-Bahlburg, 1984), a few

clinical studies of humans whose prenatal hormone environ-

ments were altered bymetabolic anomalies (Cohen-Bendahan,

van de Beek, & Berenbaum, 2005; Hines, 2004, 2010, 2011;

Jordan-Young,2012;Meyer-Bahlburg, 1984), ormaternalmedi-

cal treatment with estrogenic compounds during gestation

(Meyer-Bahlburgetal.,1995),andmostrecentlythestudiesusing

digit ratio measures to reflect the prenatal gonadal hormone

environment (Grimbos,Dawood,Burris,Zucker,&Puts,2010;

Wong&Hines, 2015). Critiques (Adkins-Regan, 1988; Balt-

hazart,2011;Hines,2011;Meyer-Bahlburg,1984;Valla&Ceci,

2011) of this perspective and its putative supportive animal

research include: (1) conflation of heterotypic sexual behavior in

animals (i.e., acceptingmounts inmalesormountingby females)

andhumanhomosexuality (e.g., themale ratwhomounts another

maleisnotconsidered‘‘homosexual,’’whilethemountedmaleis);

(2) limitations in extrapolating from phylogenetically distant ani-

mals to humans; and (3) the focus on copulatory (consummatory)

behaviorsinanimalmodelsratherthanmatepreference(appetitive)

behaviors.Additionally, studies inhumansaregenerally limitedor

complicatedbysmallsamplesize; inadequateor inappropriate

matches or‘‘control’’groups; insufficient assessment of sexual ori-

entationorhormoneexposure;mixedhormonalexposures; exoge-

nous exposure to synthetic rather than naturally occurring hor-

mones;alterationsofgenitalanatomyrelatedtohormoneexposure;

confoundswithothermetabolic andphysical correlates of intersex

conditions; and/or simultaneousexposures toother treatmentcom-

pounds.Nonetheless, there is substantial evidence that early expo-

suretosexhormonesinfluencesanatomical,physiological,and

sexually dimorphic behavioral development in animals and

humans(Cohen-Bendahanetal.,2005;Reinisch,1974;Reinisch&

Sanders, 1984, 1987; Reinisch et al., 1991). Thus, investigation of

theroleofprenatalsexhormonesinthedevelopmentofhumansex-

ual orientation incorporatingmore effective controls is warranted.

Ithasbeensuggestedthat thepotential roleofprogesterone in

mammalian sexual differentiation and development has been

insufficiently investigated (Dodd, Jones, Flenady, Cincotta, &

Crowther, 2013; Wagner, 2008). Although androgenic, estro-

genic, and antiandrogenic compounds have received attention

(includingsyntheticprogestins, someofwhichhaveandrogenic

effects), therehasbeenrelatively littleexaminationof the roleof

progesterone, despite its demonstrated antiandrogenic and antie-

strogenic effects on some systems (Dorfman, 1967; Sanders &

Reinisch,1985).Progesteroneandsyntheticprogestinsarecom-

monly prescribed during early pregnancy for luteal phase sup-

port during in vitro fertilization and for threatened abortion

(Aboulghar,2009;Bakeret al., 2014,Palagianoetal., 2004)and

later in pregnancy for prevention of premature birth and low

birth weight (da Fonseca, Bittar, Damião, & Zugaib, 2009).

Few studies have examined the long-term physical and

behavioral outcomes of either naturally occurring or synthetic

progestin exposure in humans (Cohen-Bendahan et al., 2005;

Hartwig et al., 2014; Hines, 2004, 2010; Northen et al., 2007;

Reinisch,1974,Reinisch&Sanders,1984,1987;Reinischetal.,

1991). Maternal intake of synthetic progestins and/or proges-

terone during pregnancy has been found to be associated with

increased hypospadias (urinary opening on the underside of the

penis instead of the tip) risk in males (Carmichael et al., 2005;

Dorfman, 1967; Silver, Rodriguez, Chang, & Gearhart, 1999)

and alteration of some sex-differentiated behavior patterns in

male and female offspring (Cohen-Bendahan et al., 2005; Ehr-

hardt, Grisanti, & Meyer-Bahlburg, 1977; Kester et al., 1980;

Reinisch, 1974, 1977, 1981;Reinisch&Karow,1977;Reinisch

& Sanders, 1984, 1987; Reinisch et al., 1991; Sanders & Rein-

isch, 1985).

One of these studies examined the effects of ‘‘natural’’ pro-

gesterone on sex/gender development (Kester et al., 1980). It

included 10 men (19–24years) exposed prenatally to natural

progesteronealoneandacontrolgroupmatchedondateofbirth,

age of mother, and, in most cases, prior numbers of siblings.

Progesterone-exposed subjects‘‘tended to recall boyhood behav-

iors which departed from the conventional male mode toward

‘femininity’’’and those subjects exposed to higher doses scored

loweron theBemSex-Role InventoryMasculine scale and lower

on the Feminine scale. A more recent study of fetal exposure to

prescriptiondrugsand sexualorientationdidnotfindasignificant

relationship between maternal reports of progesterone/progestin

exposure and sexual orientation, but the study was limited by its

1240 Arch Sex Behav (2017) 46:1239–1249

123

reliance on maternal recall of medical treatment often decades

earlier, among other methodological issues (Ellis & Hellberg,

2005).

Inlightofthesefindingsandthedearthofdataontheoffspring

of progesterone-treated pregnancies,we compared data on sex-

ual orientation and attraction from young adults who were

exposed in utero to progesterone (bioidentical progesterone=

C21H30O2;MW: 314.46) viamaternalmedical treatment to data

fromunexposedmatched controls.The study employeda case–

control, double-blind, prospective, longitudinal design using

membersofabirthcohortwithmatchingofcasesandcontrolson

14 physical, medical, and socioeconomic variables that were

recorded prenatally or at birth; careful evaluation of prenatal

hormone exposure; and assessment of sexual orientation and

attraction. Based upon the limited animalmodels and human

research, we hypothesized that progesterone-exposed human

offspring would show more same-sex attraction and behavior

with more exposed subjects identifying as non-heterosexual.

Method

Participants

Data from 34 subjects (17men and 17women) prenatally ex-

posed exclusively to lutocyclin and no other hormonal prepa-

ration, and their individuallymatched unexposed controlswere

drawn from an existing database, the US/Denmark Prenatal

Development Project (PDP) (Reinisch, Mortensen, & Sanders,

1993). Lutocyclin is identified as progesterone (bioidentical pro-

gesterone=C21H30O2; MW: 314.46) in the Danish Physician’s

Desk Reference (Junager & Schleisner, 1963) and was admin-

isteredduringpregnancy to treat cases of potentialmiscarriage as

indicated by staining or bleeding, abortion imminens (threatened

abortion), or maternal history of repeatedmiscarriage.Mean age

of the participants at the time of assessment for this study was

23.2years (SD=1.4).

Participants were drawn from the Copenhagen Perinatal

Cohort, comprising all 9125 offspring born at the University

Hospital in Copenhagen, Denmark, between 1959 and 1961.

During the establishment of the cohort, demographic, socioe-

conomic, and medical variables were prospectively recorded

pre-, peri-, and postnatally. Potential participants for the current

study were identified through the available computerized data-

base. Exclusion criteria were: offspring of incest; gestation

length less than 28weeks; congenital malformation (including

genital ambiguity); Down’s syndrome;maternal history of dia-

betes,epilepsyorCNSdisorder;maternaltreatmentwiththyroid

medication;maternalpsychosisorsyphilis;mother less thanage

16 at time of delivery; and mother diagnosed with polio,

encephalitis, meningitis, viral pneumonia, or ornithosis during

pregnancy. The original datatape only coded yes/no for drug

exposure in terms of the class of drug administered (hormone,

barbiturate, antiepileptic, etc.) for at least 5 days during each of

six gestational periods, coded into trimesters for these analyses.

Original hospital records for all hormone-exposed cases and

their matched controls were reviewed by our team to confirm

exclusion criteria and to obtain specific information on dosage,

timing, and duration of exposure to all gestational treatments.

All eligible cases were recruited to participate in the PDP. The

overallparticipationrateforthePDPwas87%.Extensivedetails

of the methodology are reported elsewhere (Reinisch et al.,

1993; Reinisch, Sanders, Mortensen, & Rubin, 1995). Partici-

pants only knew theywere recruited due to their inclusion in the

Danish Perinatal Cohort at birth butwere blind as to their expo-

sure status.

Of the45casesexposedto lutocyclininthePDPdatabase, the

34 included here were those exposed to lutocyclin and no other

hormonal preparation, so that anyobservedeffects of lutocyclin

would not be confounded by exposures to other hormones.

Matches were chosen from 271 non-exposed controls selected

from a large pool of similarly evaluated PDPmembers.

Matching occurred in two stages using 14 variables with

exact matching for sex. The objective of the matching was to

obtain a set of control subjectswhose distributions onmatching

variableswereascloseaspossibletothedistributionsofexposed

subjects. First, usingMahalanobismetricmatchingwithin cali-

pers defined by the estimatedpropensity score for each exposed

case, the 10 statistically best potential controls were identified

(Rosenbaum & Rubin, 1985a, 1985b) and then the Project

Director (J.M.R.)matched one or two potential controls to each

exposed case for inclusion in the study. Details of thematching

procedure have been published elsewhere (Reinisch et al.,

1993, 1995). Table 1 shows that therewere no significant group

differences (exposedvs. unexposed) in the distributions ofmat-

ching variables.

WhenthePerinatalCohortwasestablished,pregnantwomen

were interviewedas soonas theywere enrolled for prenatal care

about whether they were married or single, had planned the

pregnancy at the time of conception, or had attempted abortion

(Villumsen, 1970). For exposed cases, there was one single

mother (2.9%), one unplanned pregnancy (2.9%, not the same

person), and no abortion attempts. For the matched control

sample,23%ofthemothersweresingle,44%of thepregnancies

were unplanned, and 12% had attempted abortion. The per-

centagesfortheoverallcohortwere37,56,and7%,respectively.

It is not surprising that special treatment for pregnancy main-

tenancewas confoundedwith beingmarried, planning orwant-

ingthepregnancy,andnotattemptingabortion.Therefore, these

were not used asmatching variables.At the time, relatively few

coupleswere living togetherwithout beingmarried and being a

single mother may have presented difficulties. We do not

interpret thesepotentialconfoundsaspotentialcausativefactors

for same-sex (homosexual/bisexual) behavior and attraction. In

thePDPsampleofmorethan550participants, thesethreemater-

Arch Sex Behav (2017) 46:1239–1249 1241

123

nal variables were unrelated to offspring sexual orientation, at-

traction, or sexual behavior in either sex.

Lutocyclin exposure parameters in the present sample were

asfollows:Meantotaldosagewas915mg(SD=1073.54,range

40–5400mg)with amean treatment duration of 61days (SD=

42, range 8–158). Average daily dose was calculated for each

individualbydividingtotaldosagebydurationof treatment.The

group mean of‘‘average daily dose’’was 18.41mg/day. Forty-

onepercent(n=14)wereexposedduringthefirsttrimesteronly,

35%(n=12)during thefirstandsecondtrimesters,17%(n=6)

during the second trimester only, and 6% (n=2) during the

second and third trimesters. Table2 shows detailed informa-

tion on dosage and timing of exposure. Nominimum exposure

parameters were set for selection; thus, these represent the nor-

mal rangeofdosagesanddurationscommonlyusedin treatment

of at-risk pregnancy in Denmark during this period. Exposures

did not differ by sex. Timing of exposure occurred during peri-

odsassociatedwithsexualdifferentiationof theCNSinhumans.

Measures

Interview Data

Information on sexual orientation was obtained as part of a

structured interviewconductedbyapsychologist at the Institute

for Preventive Medicine in Copenhagen, Denmark. Psycholo-

gists were blind to the exposure status of all subjects. The fol-

lowing sexual orientation variables were addressed in the

comprehensive interview and coded as follows.

Same-Sex Variables

1. Self-labeled sexual orientation: (heterosexual/non-hetero-

sexual) [This item was drawn from a question asking par-

ticipants whether they considered themselves to be hetero-

sexual,homosexual,bisexual,‘‘don’tknow.’’Giventhesmall

numbers in the non-heterosexual categories, the data were

recoded to heterosexual/non-heterosexual for analysis.]

Table 1 Distributions of matching variables for prenatally progesterone-exposed and unexposed participants

Matching variable Exposed

n= 34

Unexposed

n= 34

Statistica p

%Maleb 50.0 50.0 na

% Firstborn 61.8 50.0 z= .85 ns

Mean (SD) gestation length (week) 37.76 (3.10) 38.12 (1.80) t(32)\1 ns Mean (SD) birth weight (g) 31.13 (8.85) 30.99 (5.06) t(33)\1 ns Mean (SD) birth length (cm) 50.97 (4.66) 50.69 (2.29) t(33)\1 ns Mean (SD) socioeconomic statusc 6.00 (1.55) 5.94 (1.52) t(31)\1 ns Mean (SD) breadwinner’s educationd 3.07 (.78) 3.06 (.74) t(29)\1 ns Mean (SD) mother’s age (year) 30.03 (4.46) 31.15 (5.76) t(33)=-1.06 ns

Mean (SD) father’s age (year) 35.00 (6.03) 33.48 (7.12) t(32)= 1.04 ns

Mean (SD) PBC 415e 33.85 (17.91) 33.53 (16.12) t(33)\1 ns Mean (SD) maternal complaint scoref 2.96 (2.48) 3.22 (2.52) t(33)\1 ns % Severe preeclampsia 3.0 2.9 z= 0 ns

%Maternal respiratory illness 2.9 2.9 z= 0 ns

Mean (SD) maternal weight gain (kg)/height cubed (m)Wgt/hght 25.52 (9.05) 25.29 (7.35) t(23)\1 ns Mean (SD) no. of cigarettes/day in third trimester 4.42 (7.01) 5.74 (7.64) t(32)\1 ns

a na=Not applicable. Unless otherwise noted df= 33 b Exact match required for sex c Family socioeconomicstatuswhen thechildwas1 yearofage.Danishsystemcategorizedonaneight-point scale, 1= lowest, 8= highest.Pairswere

exactly matched on SES, except for two exposed cases with missing data who were matched to controls with SES= 4 d Education was categorized on a four-point scale, 1= remedial instruction, 4= college e Thepredisposing riskscore is avariable in theoriginal cohortdatatape. It is ascorebasedonpregravidas factors concernedwith themother’sphysical

and emotional state prior to the pregnancy. Information includes such items aswhether themother wasmarriedwhen she conceived, whether she had

previously had an abortion, a miscarriage, a stillbirth, or neonatal death; her age; her weight; and previous history of central nervous system illness,

syphilis, cardiovascular illness, or diabetes. The score indicates that conditions (physical and emotional) were probably ‘‘less than optimum’’ for

conception at the time. For the cohort, the scores range from 0 to 130 and the mean is 29.52 f Thematernal complaint score included the following: severepreeclampsia, hypertension, prescriptionofdiuretics, edemaandproteinuria, bleeding/

staining, allergies and treatment with antihistamines, and anemia

1242 Arch Sex Behav (2017) 46:1239–1249

123

2. Lifetime attraction to own sex: (yes/no)

3. Current attraction to own or both sexes: (yes/no)

4. Kissed own sex: (yes/no)

5. Having been partially undressed in a sexual situationwith

own sex: (yes/no)

6. Havingbeen fullyundressed inasexual situationwithown

sex: (yes/no)

7. ‘‘Intercourse’’with own sex: (yes/no) [Our interview data

indicated that women generally interpreted this question

to mean mutual genital sexual stimulation; men usually

interpreted this as anal intercourse.]

Other-Sex Variables

8. Having kissed other (‘‘opposite’’) sex: (yes/no and age at

first engagement)

9. Having been partially undressed in a sexual situationwith

other sex: (yes/no and age at first engagement)

10. Having been fully undressed in a sexual situation with

other sex: (yes/no and age at first engagement)

11. Intercoursewith other sex: (yes/no, and age at first engage-

ment).

Items 4–11 were coded from questions asking age at first par-

ticipation in each behavior, an approach developed by Kin-

sey (Kinsey et al., 1948;Kinsey, Pomeroy,Martin,&Gebhard,

1953). Asking age at first engagement signals participants that

one is non-judgmental about their engagement in particular

sexualbehaviors.Apostpubertal criterionwasapplied forageat

first engagement in thesebehaviors. Specifically, age at puberty

(whichwasassessedbyaseparatesetofquestionsaboutmarkers

ofpuberty)wascomparedtothereportedageatfirstengagement

in the behaviors. The very few reports of behaviors prior to

puberty were not included in these analyses as they could have

been childhood sexual exploration. This criterion was consis-

tently applied across all subjects and for both same-sex and

other-sex behaviors. The number of participants engaged in the

same-sexbehaviorswasinsufficient toconductastatisticalanal-

ysisofagefor thosevariables.However,wewereable toanalyze

age at first engagement in the heterosexual behaviors.

Questionnaire Data

Sexual Behavior Inventory (SBI) This self-administered

questionnaire was created for the PDP (Reinisch et al., 1993)

to assess whether or not 67 different sexual behaviors have

been tried. Three items on the questionnaire were relevant to

sexual orientation: (1) to ‘‘go to bed with’’ a person of your

own sex (in Danish, this item is understood to mean inter-

course or mutual genital contact); (2) to masturbate in the

presence of another person(s) of the same sex; and (3) to

masturbate in the presence of another person(s) of the oppo-

site sex.

SexualAttitudesQuestionnaire (SAQ) This self-administered

questionnaire, created for the PDP (Reinisch et al., 1993),

includes 120 items from the original Eysenck Inventory of

Attitudes towardSex (Eysenck, 1976). Participants indicated

their agreement/disagreement on a three-point scale (yes, ?,

no; scored 2, 1, 0, respectively) with 179 statements about

various aspects of sexuality. There are two factors relevant to

sexual orientation: attraction tomales and attraction to females.

Each factor has six items and shows good internal consistency

(Cronbach’s alphas .88 for attraction tomales and .90 for attrac-

tion to females). Items for attraction to males and attraction to

femaleswereworded identically except for the sex of the object

of attraction. Questions (in Danish) were scattered throughout

the SAQ. The 12 questions about attraction to males/females

translated into English are as follows:

• IusuallytakealonglookwhenImeetanattractiveman/woman in the street.

• Male/female sexual organs are attractive. • I often have fantasies about male/female sex partners. • Now and then I think about sex when I am in an attractive man’s/woman’s company.

• I sometimes have fantasies about being with two or more men/women at the same time.

• I regularly meet men/women whom I find attractive.

Table 2 Descriptive statistics for progesterone exposure variables (n= 34)

Progesterone exposure variables N (%)

Timing of exposure (trimesters)

1st only 14 41.2

1st–2nd 12 35.3

2nd only 6 17.6

2nd–3rd 2 5.9

3rd only 0 0.0

Total dosage (mg)

40–300 11 32.4

301–999 14 41.2

1000–1999 5 14.7

2000–5400 4 11.8

Duration of exposure (days)

8–29 9 26.5

30–60 12 35.3

61–120 8 23.5

121–158 5 14.7

Average daily dosage (mg/day)

3–9 16 47.1

10–25 7 20.6

26–50 11 32.4

Arch Sex Behav (2017) 46:1239–1249 1243

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Procedure

Thestudywasapprovedbytheappropriatereviewboardsforthe

protectionofhumansubjects inboth theU.S.andDenmark.The

data presented in this article assessing sexual orientation rep-

resent a subset of a large evaluation battery (Reinisch et al.,

1993).Thepurposeandproceduresfor thestudywereexplained

to participants, and informed consent was obtained. A psychol-

ogist supervised the collection of questionnaire data and con-

ducted the interview during a full day of evaluation at the Insti-

tute for PreventiveMedicine. Evaluators and participants were

blind regarding treatment status.

Data Analysis

We hypothesized that same-sex behavior and attraction would

be higher for the exposed compared to the unexposed partici-

pants. Data were first examined for interactions between sex of

participant and exposure to lutocyclin. Finding none, data from

men and women were then combined for statistical analysis of

exposure effects, with the exception of scores for attraction to

males and attraction to females as these are more easily under-

stoodwhen presented separately by sex. For dichotomous vari-

ables, Tango’s (1998) test of the differences in proportions in

matchedpairswas used.Unlike theMcNemar test, Tango’s test

accommodates292 tableswithoff-diagonal zerocells. For con-

tinuous variables, paired t tests were performed to compare data

from exposed and unexposed participants. Spearman’s rho was

used to evaluate the correlation between attraction to males and

attraction to females. Relationships between progesterone treat-

ment parameters and outcomes of interest were assessed by the

Kolmogorov–SmirnovZ testofequalityofdistributions.We

report p values for two-tailed tests, a conservative criterion

given our directional hypotheses which would justify use of

one-tailed tests.

Results

As shown in Table 3, compared to their matched controls,

exposedcasesshowedaconsistentpatternofhigherpercentages

of:

1. Self-labeled identification as other than heterosexual (i.e.,

homosexual, bisexual, or‘‘don’t know’’) (20.6% exposed,

0% controls, p\.01). Among the exposed men, one iden- tified as homosexual, two as bisexual, and two said‘‘don’t

know.’’Among exposed women, two identified as bisex-

ual. All other subjects, exposed and unexposed, self-iden-

tified as heterosexual;

2. ‘‘Ever Attracted to Own Sex’’ (29.4% exposed, 5.9%

controls, p= .02);

3. ‘‘Currently Attracted to Own or Both Sexes’’ (17.6% ex-

posed, 2.9% controls, p\.06); and 4. Various sexual behaviors with their own sex including

‘‘kissed own sex’’; partially and fully undressed in a sexual

situation; ‘‘intercourse’’; ‘‘gone to bed’’; and ‘‘masturbated

together’’ (range 14.7–24.2% exposed cases, 0–9.1% of

controls). In general, behavioral patternswere consistent for

individuals. For example, all those reporting ‘‘intercourse’’

with a person of the same sex also reported ‘‘going to bed’’

with; being fully and partly undressed in a sexual situation

with; and kissing someone of the same sex.

None of those who identified as other than heterosexual had

own sex attractions or engaged in these same-sex behaviors

were concordant with their matches.

Exposure status was not associated with heterosexual expe-

rience—all participants reported sexual behaviorwith the other

sex.Thesmallnumberofcaseswhoengagedinsame-sexsexual

behaviorsprecludedstatisticalanalysesof‘‘AgeatFirstEngage-

ment’’ in those behaviors, but this measure for heterosexual

behaviorsdidnotdifferaccordingtoexposurestatus(seeTable4).

For men, scores on the attraction to males scale were signif-

icantly higher for exposed cases compared to controls, paired

t(16)=2.76,p\.02, two-tailed, but scores did not differ for the attraction to females scale (see Table5). For women, scores on

attraction to females scale were not different between exposed

and unexposed cases, but there was a statistical trend toward

higher scores on the attraction to males scale for exposed

women,paired t(16)=1.92,p= .07, two-tailed.Thus,exposure

was positively associatedwith higher scores on the attraction to

males scale regardless of sex, total group ofmales, and females

combined paired t(33)=3.31, p\.01, two-tailed. Although a bipolarmodelof sexualorientation(Kinseyetal.,1948;Sanders

et al., 1990)would predict a strongnegative relationshipbetween

scale scores for attraction to males and attraction to females, this

was not the case (for men, Spearman’s rho=-.10; for women,

rho= .23; both ns).

In light of findings linking birth order and number of older

brothers to homosexual orientation among men (Blanchard &

Bogaert, 1996; Cantor, Blanchard, Paterson,&Bogaert, 2002),

this possible confound was examined. Neither birth order nor a

number of older brothers confound the current findings. Not

surprisinggiven thematching,birthorderdidnotdifferbetween

exposed and unexposed men (M=1.76, SD= .96) and the

numberwhohadolderbrotherswasthesamefortheexposedand

unexposed groups (n=5 for each group).

A systematic investigation of the relationship between pro-

gesterone treatment parameters (i.e., total dosage, averagedaily

dosage, timing,anddurationofprogesteroneexposure)andout-

comesof interestwasprecludedby thehighvariability inmater-

nal medical treatment and the intercorrelations among the var-

ious treatmentparameters.Nonetheless, it isnoteworthy that the

seven individualswho self-identified as other thanheterosexual

1244 Arch Sex Behav (2017) 46:1239–1249

123

wereexposed tohigher totaldosages (median=1000mg, range

450–5400mg)overlongerdurations(median=105days,range

20–120days) than thosewhoidentifiedasheterosexual (median

total dosage=500mg, range 40–2700mg, K–S Z=-2.28,

p= .02; median duration=47days, range 8–158days, K–S

Z=-2.24, p\.03).

Discussion

In summary,we observed consistent findings across samples of

menandwomenprenatally exposed to exogenousprogesterone

for a set of variables directly reflective of sexual orientation.

Relative to unexposed controls, prenatal exposure to proges-

terone was significantly associated with: (1) decreased likeli-

hood of self-identification as heterosexual; (2) increased like-

lihood of having engaged in same-sex sexual behaviors; (3)

increased likelihood of reporting attraction to the same or both

sexes,and(4)higherscoresontheattractiontomalesscale.Pro-

gesterone exposurewas not associatedwith a decrease inmea-

sured heterosexual behavior.Amongprogesterone-exposed cases,

non-heterosexual identity was shown to be associated with higher

total dosages and longer duration of prenatal exposure to proges-

terone.

We recognize thatmany factorsmay affect the development

of sexual orientation and that the prenatal hormone environ-

ment is only one of these. In considering the epigenetic mech-

anism(s) bywhich prenatal exposure to exogenous progesterone

may influence sexual orientation, it is relevant that progesterone

appears to have both antiandrogenic and antiestrogenic potential

duringearlycriticalorsensitiveperiodsofdevelopment(Connolly,

Handa,&Resko,1988;Dorfman,1967;Kesteretal.,1980;Sanders

Table 3 Comparison of sexual orientation, attraction, and behavior variables for prenatally progesterone-exposed (Exp) and unexposed (Un) participants

Men

(17 pairs)

Women

(17 pairs)

Total group

(34 pairs)

z Statistica p (two-tailed)b

Exp Un Exp Un Exp Un

n n n n n (%) n (%)

Same sex

Non-heterosexual self-labeled identityc,d,e 5 0 2 0 7 20.6 0 0 2.56 .008

Ever attracted to own sexc 6 0 4 2 10 29.4 2 5.9 2.31 .021

Current attraction to own or both sexesc,e 3 0 3 1 6 17.6 1 2.9 1.88 .059b

Kissed own sexc,e 3 0 4 1 7 20.6 1 2.9 2.12 .034

Has been partially undressed in a sexual situation with own sexc,e,f 3 0 4 1 7 20.6 1 2.9 2.12 .034

Has been fully undressed in a sexual situation with own sexc,e,f 2 0 4 1 6 17.6 1 2.9 1.88 .059b

‘‘Intercourse’’with own sexc,e,f 2 0 3 0 5 14.7 0 0 2.23 .025

‘‘Gone to bed’’with person of own sexe,f,g 2 0 4 1 6 17.6 1 2.9 1.89 .059b

Masturbated in the presence of same sexg 6 2 2 1 8 24.2 3 9.1 1.67 .095b

Other (‘‘opposite’’) sex

Kissed other sexc 17 17 17 17 34 100 34 100 na na

Has been partially undressed in a sexual situation with other sexc 17 17 17 17 34 100 34 100 na na

Has been fully undressed in a sexual situation with other sexc 17 17 17 17 34 100 34 100 na na

Intercourse with other sexc,h 16 17 17 17 33 97.1 34 100 1.00 ns

Masturbated in the presence of other sexg 6 8 4 6 10 30.3 14 42.4 1.15 ns

a Tango’s (1998) test of the differences in proportions in the pair-sample design was used (na = Not applicable) b We have used a conservative criterion for statistical significance. The hypotheses are directional, and therefore, one-tailed tests may be justified. If

one-tailed tests are used, all same-sex variables in this table would be significant at p\.05 (na = Not applicable) c From the interview d Self-identification as lesbian, homosexual, bisexual, or‘‘don’t know’’was recoded as non-heterosexual. Specifically, among the exposed men one

identified as homosexual, two as bisexual, and two said‘‘don’t know.’’Among exposedwomen, two identified as bisexual. All other subjects, exposed

and unexposed, self-identified as heterosexual e Noneof thosewho identifiedasother thanheterosexual; hadownsexattractions; or engaged in these same-sexbehaviors,were concordantwith their

matches f In general, behavioral patterns were consistent for individuals. For example, all those reporting ‘‘intercourse’’with a person of the same sex, also

reported‘‘going to bed’’with, being fully and partly undressed in a sexual situation with, and kissing someone of the same sex g From the Sexual Behavior Inventory h Only one participant, a lutocyclin-exposed man (who reported same-sex‘‘intercourse’’), did not report having had heterosexual intercourse

Arch Sex Behav (2017) 46:1239–1249 1245

123

& Reinisch, 1985). Exogenous progesterone has been demon-

strated to have physiological effects during gestation despite the

presenceofhighendogenous levels (Aboulghar, 2009; daFonseca

et al., 2009; Palagiano et al., 2004; Silver et al., 1999). Exogenous

progesterone administrated in associationwith invitro fertilization

hasbeen suggested as a factor in increased rates of hypospadias in

malenewborns (Carmichael et al., 2005;Dorfman,1967;Silver

et al., 1999). Additionally, emerging researchwith rodents sug-

gests progesterone andprogesterone receptorsmayplay an impor-

tant role in thedevelopmentofdimorphic sexual, cognitive, social,

and affective behavior differentiation (Wagner, 2008; Wagner,

Nakayama, & De Vries, 1998). While the direct physiological

mediators of the effects of prenatal progesterone exposure await

identification,ourfindingsmaybeconsideredabehavioralbioas-

say of such underlying effects (Reinisch, 1974; Reinisch et al.,

1991). This bioassay makes it clear that exposure to exogenous

progesterone during a sensitive period of humanCNS differenti-

ationmaypermanentlyaffectneuralfunctionandultimatelyinflu-

ence later behavior. It is also possible thatmedical treatmentwith

progesterone isamarkerofmaternalprogesteronedeficiencyand

thatvariation inendogenousmaternalprogesterone levelsmaybe

animportantfactorinnaturallyoccurringdifferencesinsexualori-

entation. The detection of a relationship between prenatal expo-

sure to exogenous progesterone and sexual orientation in early

adulthood,despitemanyinterveningfactors,supports thehypoth-

esis that the prenatal hormone environment is influential.

Howmight the addition of exogenousprogesterone into an

already rich mixture of gestational steroids, including endoge-

nous progesterone, affect the nervous system and subsequent

behavioral development of the offspring? First, in keepingwith

themostcurrentclinicalresearch,thishormonalmedicationwas,

and continues to be, administered by physicians to treat symp-

tomsof staining,bleeding, topreventprematurity in twins (Rouse

etal.,2007;Schuitetal.,2015),andtopreventpretermbirth(Dodd

et al., 2013; Merlob, Stahl, & Klinger, 2012) and for imminent

spontaneousabortion(daFonsecaetal.,2009).Thisdemonstrates

its capacity to have some meaningful physiological impact. It is

currentlyusedforpain,uterinecontractions,andinadequateluteal

phase, and its effectiveness has been demonstrated on both ultra-

sound assessment of uterine contraction and a pain scale (Pala-

gianoetal.,2004).Second,progesteronewasadministeredexoge-

nously at pharmacological levels during periods of gestation

known to be sensitive to the influence of steroid hormones on

sexualdevelopment(seeTable2).Third,exogenouslyintroduced

hormonesmaydiffer from (and thus have different potency than)

their endogenous counterparts in how they aremetabolized, their

receptor affinity and sensitivity, and their systemic versus local-

ized action. Thus, it is possible that, compared to endogenous

levels, even relatively limited physiological dosesmay have sig-

nificant effects on various systems when administered exoge-

nously.

Table 4 Comparison of ages of first engagement in sexual behaviors with other sex for prenatally progesterone-exposed and unexposed participants (34 pairs)

Other-sex variable Exposed Unexposed Paired t p

M (SD) M (SD)

Age at first kissing other sex (years) 13.81 (2.77) 13.10 (.40) 1.21 ns

Age at first being partially undressed in a sexual situation with other sex (years) 14.82 (2.43) 14.10 (2.60) 1.33 ns

Age at first being fully undressed in a sexual situation with other sex (years) 15.72 (2.50) 14.97 (2.43) 1.35 ns

Age at first intercourse with other sex (years) 16.39 (2.29) 15.81 (2.75) 1.02 ns

Table 5 Comparison of scores for attraction to males and attraction to females for prenatally progesterone-exposed (Exp) and unexposed (Un) participants within sex

Score Males (17 pairs) Females (17 pairs)

Exp Un Paired t p (two-tailed) Exp Un Paired t p (two-tailed)

Attraction to males

M .52 .13 2.76 .014 1.57 1.40 1.92 .073

SD .56 .18 .29 .48

Attraction to females

M 1.76 1.81 \1 ns .75 .58 \1 ns SD .43 .23 .54 .51

Possible scores ranged from 0 to 2

1246 Arch Sex Behav (2017) 46:1239–1249

123

A limitation common to studies of sexuality is their reliance

on self-report. The non-normative status of same-sex attraction

andbehavior tends toproduce a social desirability effect toward

underreporting these behaviors. Any such bias would have

servedtominimizedifferencesbetweengroups.Similarly,small

sample size often results in limited statistical power. It is also

important to note that in research on human prenatal exposures,

our34caseswithasingleunconfoundedtypeofhormonalexpo-

sure represent an unusually large number. More detailed eval-

uationsoftreatmentparameterswerenotpossiblegiventhewide

range of individual treatment regimes and the colinearity of the

treatmentvariables.Despitethevariationintreatmentregimens,

theextensivecomparableprospectivedataavailableonbothindex

cases and controls provide confidence in the treatment status for

bothgroupsanda relatively largepoolofmatchingvariables.Our

groups were carefully matched on 14 highly relevant prenatal,

perinatal, and maternal factors which should serve to minimize

confounds incomparisonsbetweenexposedandcontrol subjects.

It shouldbe taken intoaccount thatparticipantswere in their early

to mid-20s when evaluated and that the lifetime range of their

patterns of sexual behavior and attractionswas not likely to have

been fully realized by early adulthood. Follow-up studies would

be required to evaluate the levels of same-sex behavior and/or

attraction thatmay have been revealed in subsequent decades. In

keeping with the strengths of the current design, we found con-

sistent statistically significant effects across a number of different

measures supporting our hypotheses.

What are the theoretical implications of our findings regard-

ing the conceptualizationof the nature of sexual orientation and

its biological bases?Support for the commonlyheldbipolarmodel

of sexual orientation (a unidimensional model where one pole

representshomosexualityand theother, heterosexualityormas-

culinity vs. femininity; Kinsey et al., 1948) requires a strong

negative correlation between scale scores on attraction tomales

and attraction to females (Sanders et al., 1990) as well as that

betweensameandopposite sexexperience.However, our study

fails to support thismodel since inbothmales and females these

correlationswerelowandnotsignificant.Therefore,wehypoth-

esize that sexual orientation may be more accurately and pro-

ductively conceptualized in terms of a two-dimensional model

in which the dimensions of heterosexuality and homosexuality

are relatively independent, with each dimension having a high

and low pole, perhaps reflecting different neurodevelopmental

pathways (Olvera-Hernandez, Chavira, & Fernandez-Guasti,

2015;Sandersetal.,1990;Storms,1988).Suchaperspectivefits

well with similar models we have described for the differentia-

tion of masculinity and femininity in the context of the devel-

opment of more general aspects of gender identity and role

(Reinisch & Sanders, 1987; Reinisch et al., 1991). Method-

ologically, our results emphasize that studies of sexual

expression,whichfocusonsame-sexor‘‘opposite’’-sexbehavior

to the exclusion of the other, may obscure the prevalence of

bisexual patterns.

In conclusion, these findings reveal that prenatal progester-

onehasbeenanunderappreciatedfactor inhumanpsychosexual

development (as are the actions of fetal testosterone or extern-

ally introduced endocrine disruptors). Our findings suggest

that natural perturbations in endogenous progesterone dur-

inggestationmayaffect individual differences in the expres-

sionofadultsexualorientation.Specifically,progesteroneexpo-

surewas found to be related to increased non-heterosexual self-

identification,attraction to thesameorbothsexes,andsame-sex

sexual behavior. The findings challenge the prevailing view of

homosexual interest andbehaviorasa simple reflectionof femi-

nization/demasculinization in males and masculinization/de-

feminizationinfemales.Incontrast,thecurrentresearchunderli-

nes thenecessityofconcurrentmeasurementofawidespectrum

of both same-sex and‘‘opposite’’-sex behaviors and attitudes in

any study of human sexual expression.

The current findings highlight the likelihood that prenatal

exposuretoprogesteronemayhavelong-termbehavioralseque-

lae related to sexuality in humans, even in the absence of mor-

phologicaleffectsonthegenitalia. Inlightof thecontinuedtreat-

ment of human pregnancies with progesterone (and other pro-

gestogens), further studies of offspring of progesterone-treated

pregnancies are warranted and may provide important insights

into the role of this hormone in human behavioral development

(Dodd et al., 2013).

Acknowledgements WethankLeonardA.Rosenblum for editingof the article, CarolynS.Kaufman for research assistanceduringdata collection

and archiving, and Brandon Hill for assistance with literature searches.

Funding This research was supported in part by US Public Health Ser- viceGrantsDA05056toJMRandSAS,GrantsHD17655andHD20263to

JMR, Grant 9700093 from the Danish Research Councils to ELM. Some

preliminary analyses of a portion of the complete data presented in final

form in this paper were previously described in a thesis by Caroline Ripa,

University of Copenhagen, 2002.

Compliance with Ethical Standards

Conflict of interest The authors declare that they have no conflict of interest.

Ethical Approval Existing data from human research participants were used. All procedures performed in studies involving human participants

were in accordance with the ethical standards of the institutional and/or

national researchcommitteeandwith the1964HelsinkiDeclarationand its

later amendments or comparable ethical standards.

Informed Consent At the time of data collection, informed consent was obtained from all individual participants included in the study.

Arch Sex Behav (2017) 46:1239–1249 1247

123

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