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

123

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 re

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